THE  LIBRARY 

OF 

THE  UNIVERSITY 
OF  CALIFORNIA 

PRESENTED  BY 

PROF.  CHARLES  A.  KOFOID  AND 
MRS.  PRUDENCE  W.  KOFOID 


TEXTBOOK 


OF 


PHAEMACOLOG-T 


AND 


THEEAPEUTICS 


OR   THE 


ACTION  OF  DRUGS  IN  HEALTH  AND  DISEASE 


BY 

ARTHUR  R.   CUSHNY,  M.A.,  M.D.,  ABERD. 

PROFESSOR  OF  PHARMACOLOGY  IN  THE  UNIVERSITY  COLLEGE,  LONDON,  ENG.  ;  FORMERLY  PRO- 
FESSOR OF   MATERIA  MEDICA  AND  THERAPEUTICS  IN  THE  UNIVERSITY  OF  MICHIGAN; 
THOMPSON  FELLOW  IN  THE  UNIVERSITY  OF  ABERDEEN  AND  ASSISTANT  IN  THE 
PHARMACOLOGICAL  INSTITUTE  OF  THE  UNIVERSITY  otf  STRASSBURG. 


FOURTH   EDITION,  THOROUGHLY   REVISED. 
ILLUSTRATED  WITH  FIFTY-TWO  ENGRAVINGS 


LEA  BROTHERS  &  CO. 
PHILADELPHIA  AND  NEW  YORK 


Copyright,  1906,  by 
LEA   BROTHERS    &   CO. 


Authority  to  use  for  comment  the  Pharmacopoeia  of  the  United  States 
of  America  (Eighth  Decennial  Eevision),  in  this  volume,  has  been  granted 
by  the  Board  of  Trustees  of  the  United  States  Pharmacopreial  Convention  ; 
which  Board  of  Trustees  is  in  no  way  responsible  for  the  accuracy  of  any 
translations  of  the  Official  Weights  and  Measures,  or  for  any  statement  as 
to  strength  of  Official  Preparations. 


K-  R3  I  <*  7 


OSWALD  SCHMIEDEBERG, 


MEISTER,  YOM  SCHULKK  GEWIDMET. 


PREFACE  TO  THE  FOURTH  EDITION. 


THE  revision  of  the  United  States  Pharmacopoeia  has  necessitated 
the  issue  of  a  new  edition  of  this  text-book,  and  the  opportunity  has 
been  taken  to  record  such  advances  in  the  subjects  of  Pharmacology 
and  Therapeutics  as  have  been  made  in  the  last  two  years.  In  order 
to  permit  of  this  being  done,  and,  in  particular,  to  admit  of  references 
to  the  newer  literature  of  the  subject,  some  of  the  older  bibliography 
has  been  curtailed.  As  a  general  rule,  the  new  authors  quoted  have 
given  references  to  their  predecessors,  but  in  some  instances  it  may  be 
necessary  to  refer  to  the  earlier  editions  in  order  to  complete  the  bibli- 
ography. The  changes  made  in  the  text  are  too  numerous  to  be 
detailed  here,  but  perhaps  attention  may  be  called  to  the  new  features 
brought  out  by  Embley  and  others  in  regard  to  the  action  of  chloro- 
form and  its  dangers,  and  to  the  change  in  the  views  held  as  to  the 
effects  of  wood -alcohol  in  man. 

The  index  of  drugs,  classified  according  to  their  therapeutic  uses, 
has  been  retained  in  view  of  its  manifest  usefulness. 

I  have  to  express  again  my  appreciation  of  the  kindness  of  many 
friends  who  have  aided  me  by  suggestions,  and  to  record  my  indebted- 
ness to  Dr.  W.  J.  McNeal  for  reading  the  proofs  of  this  edition. 

A.  E.  C. 


PREFACE  TO  THE  FffiST  EDITION. 


THE  following  pages  were  written  to  supply  a  want  which  I  have 
felt  keenly  in  teaching  the  subject  of  pharmacology  to  students  who 
have  completed  the  purely  scientific  branches  of  medicine  and  are  be- 
ginning their  clinical  studies.  My  object  has  been  to  bridge  over  the 
hiatus  which  exists  between  the  phenomena  occurring  in  the  normal 
organism  and  those  which  are  elicited  in  the  therapeutic  use  of  drugs, 
to  show  how  far  the  clinical  effects  of  remedies  may  be  explained  by 
their  action  on  the  normal  body,  and  how  these  may  in  turn  be  cor- 
related with  physiological  phenomena.  It  necessarily  follows  that  the 
subject  is  treated  from  the  experimental  standpoint,  and  that  the  re- 
sults of  the  laboratory  investigator  are  made  the  basis  of  almost  every 
statement.  Where  these  fail  to  elucidate  the  therapeutic  effects  or 
even  to  suggest  a  possible  explanation,  I  have  preferred  to  leave  the 
question  undiscussed  rather  than  to  call  on  such  occult  del  ex  machina 
as  alterative  or  tonic  actions. 

Two  great  difficulties  present  themselves  at  the  outset  to  the  writer 
on  pharmacology  who  is  not  satisfied  to  take  his  statements  at  second 
hand,  or  to  formulate  explanations  from  his  unaided  inner  conscious- 
ness ;  these  are  the  overwhelming  literature  on  the  subject,  and  the 
wide  limits  of  the  field  of  study.  As  regards  the  first,  I  have  read,  as 
far  as  was  in  my  power,  the  original  papers  of  importance,  and  in  order 
to  facilitate  the  work  of  others  who  may  wish  to  follow  this,  the  only 
satisfactory  method  of  study,  have  appended  a  bibliography  to  each 
chapter.  It  was  impossible  within  the  limits  of  a  textbook  to  make 
this  complete,  or  even  to  enumerate  more  than  a  few  of  the  works  con- 
sulted, and  I  have  accordingly  selected  those  which  appeared  most 
important,  and  those  which  were  furnished  with  the  most  complete 
bibliography. 

As  regards  the  scope  of  the  work,  I  have  attempted  to  give  the 
present  standpoint  of  knowledge  of  such  bodies  as  are  of  therapeutic  or 
toxicological  interest,  and  also  of  those  which,  possessing  in  themselves 
no  immediate  interest  in  practical  medicine,  have  thrown  important 
light  on  biological  problems,  and  are  accordingly  likely  to  be  referred 
to  in  scientific  literature. 


•8  PREFACE. 

Unfortunately,  a  writer  on  this  subject  cannot  as  yet  restrict  his  at- 
tention to  these  classes,  but  must  refer  at  more  or  less  length  to  many 
drugs  which  possess  little  interest  either  from  a  therapeutic  or  a  scien- 
tific point  of  view.  It  is  true  that  the  more  advanced  teachers  of 
medicine  have  very  properly  abbreviated  their  lists  of  remedies,  until 
those  generally  employed  may  be  enumerated  in  units  where  they  were 
once  counted  in  scores,  but  the  student  on  going  into  practice  meets 
numbers  of  drugs  previously  unknown  to  him,  and  not  appreciating 
that  these  have  already  been  tried  and  discarded  by  his  teachers,  is 
tempted  to  fall  into  the  slough  of  unreasoning  empiricism.  There  is 
still  a  tendency  even  among  the  educated  to  ascribe  therapeutic  virtues 
to  every  new  weed  and  every  new  product  of  chemical  industry,  and 
the  teacher  of  pharmacology  must  not  only  point  out  the  good,  but  has 
the  more  ungrateful  task  of  condemning  the  worthless.  The  period  of 
constructive  pharmacology  has  scarcely  dawned ;  at  present  its  chief 
function  is  destructive  and  critical. 

In  dealing  with  each  drug,  I  have  attempted  to  unify  the  whole  ac- 
tion by  using  the  most  distinctive  feature  as  a  centre  around  which  to 
group  the  less  important  symptoms.  Where,  as  is  often  the  case, 
there  is  a  divergence  of  views  among  authorities,  I  have  generally  pre- 
sented only  one  side  of  the  question,  except  in  very  important  subjects. 
This  dogmatic  method  has  of  course ,  its  drawbacks,  but  is,  I  think, 
preferable  to  involving  the  student  in  a  labyrinth  of  arguments  and 
counter-arguments,  the  respective  weight  of  which  he  is  quite  unable 
to  estimate. 

The  preparations  enumerated  are  those  included  in  the  United  States 
and  the  British  Pharmacopoeias,  and  such  others  as  seemed  of  sufficient 
importance.  I  have  attempted  to  indicate  by  special  type  (small  capi- 
tals) those  that  are  more  generally  used. 

Some  explanation  may  seem  necessary  for  the  introduction  of  the 
word  "  therapeutics  "  in  the  title,  in  view  of  the  fact  that  pharmacology 
is  stated  in  the  introduction  to  embrace  all  that  part  of  therapeutics 
which  can  be  treated  of  apart  from  clinical  lectures.  This  definition 
is  not  universally  used,  however,  and  it  has  been  felt  advisable  to  in- 
dicate more  distinctly  the  scope  of  the  work  by  adding  the  more 
familiar  term. 

To  those  acquainted  with  the  Grundriss  der  Arzndmittellehre  of 
Schmiedeberg,  it  is  unnecessary  to  state  that  this  volume  has  been 
largely  inspired  by  that  classical  work.  Some  chapters  may  in  fact 
be  regarded  as  merely  expansions  of  those  issued  from  the  Strassburg 
laboratory,  but  this  must  necessarily  be  the  case  in  any  work  which 


PREFACE.  9 

pretends  to  treat  the  subject  from  the  experimental  standpoint.  The 
use  of  such  a  model  naturally  exposes  the  writer  to  the  criticism  that 
he  has  fallen  short  of  the  original  standard,  especially  when  such 
divergences  are  made  from  it  as  occur  in  this  work.  But  if  I  have 
departed  from  the  letter  in  some  respects,  I  hope  that  at  least  the  spirit 
of  the  Grundriss  has  been  preserved  in  these  pages.  .  I  must  acknowl- 
edge my  indebtedness  for  references  to  papers  which  might  have 
otherwise  escaped  my  notice  to  the  following  textbooks :  Kobert's 
Lehrbuch  der  Intoxicationen,  Lewin's  Nebenwirkungen  der  Arzneimittel, 
Husemann's  Pflanzenstoffe,  Harnack's  Arzneimittettehre,  H.  C.  Wood's 
Therapeutics,  its  Principles  and  Practices  and  Stokvis'  Leqons  de  Phar- 
macotherapie. 

Finally,  I  have  much  pleasure  in  acknowledging  the  assistance  of  my 
colleagues  in  the  preparation  of  this  work,  particularly  that  of  Profes- 
sor Huber,  who  furnished  several  of  the  illustrations.  Dr.  G.  B. 
Wallace  has  put  me  under  lasting  obligations  through  the  patience  and 
care  which  he  has  bestowed  on  the  tedious  task  of  proof-correction, 
and  I  must  thank  Dr.  W.  Mogk  also  for  his  assistance  in  this  part  of 
the  work. 

UNIVERSITY  OF  MICHIGAN, 
ANN  ARROR,  MICH.,  June,  1899. 


CONTENTS. 


PAGE. 
Introduction. 17 

Mode  of  action  of  drugs,  stimulation,  depression,  irritation  .  .  20 
Elective  affinity  of  drugs,  protoplasm  poisons  ....  22 

Remote,  local  and  general  action 23 

Chemical  composition  and  pharmacological  action  ...  24 
Conditions  modifying  the  effects  of  drugs  .....  25 
Methods  of  administration  ........  30 

Chemical  characters  of  drugs 34 

Pharmacopoeias  and  pharmacopceial  preparations .  ...  37 
Classification  of  drugs  , ,41 


PAKT   I. 

ORGANIC      SUBSTANCES     WHICH     ARE      CHARACTERIZED 

CHIEFLY   BY   THEIR   LOCAL   ACTION          ....  45 

1.  Demulcents    ...........  45 

2.  Emollients .         .         .49 

3.  Sugars  and  flavoring  substances      .......  54 

4.  Simple  bitters 55 

5.  Volatile  oil  series    .         . 61 

Flavoring  agents  and  carminatives. 66 

Pepper  group. 72 

Malodorous  volatile  oils 73 

Genito-urinary  disinfectants 74 

Uva  ursi 77 

6.  Skin  irritants  and  counter-irritation 78 

Turpentine  oil  group 85 

Mustard 88 

Cantharidin  series  .                  89 

7.  Vegetable  purgatives 93 

Purgative  oils.         .                  97 

Anthracene  purgatives .99 

Jalapin  and  colocynthin  group 103 

8.  Vegetable  astringents — tannic  acid  group        .....  109 

9.  Anthelmintics 115 

Male  fern 116 

Cusso 118 

Granatum 119 

Santonin  120 


14  CONTENTS. 

PAGE; 

22.  Charcoal 578 

23.  Boracic  acid  and  borax 578 

24.  Carbonic  acid 580 

25.  Chlorine  and  bromine 582 

26.  Oxygen 585 

27.  Peroxide  of  hydrogen      .........  587 

28.  Phosphorus 591 

29.  Arsenic  .                                                                                             .         ,  603 


PAKT   IY. 

THE   HEAVY  METALS 621 

1.  Antimony 629 

2.  Mercury 634 

3.  Iron 655 

4.  Lead 670 

5.  Copper 680 

6.  Zinc 683 

7.  Silver 686 

8.  Bismuth 692 

Cerium 695 

9.  Aluminium  and  alum 695 

10.  Minor  metals 698 

Gold 698 

Platinum 698 

Chromium 699 

Manganese      ...........  700 


PAKT   V. 

FERMENTS,    SECRETIONS   AND   TOXALBUMINS       .         .         .705 

1.  Digestive  ferments .         .........  705 

Pepsin 705 

Pancreatic  ferments 706 

Vegetable  ferments 707 

Diastase 707 

2.  Bile 708 

3.  Internal  secretions . 710 

Thyroid  gland 711 

Other  internal  secretions 718 

4.  Toxalbumins 720 

5.  Cod-liver  oil 722 

6.  Phloridzin  .         .         -         .725 


PART   VI. 
MENSTRUA  AND   MECHANICAL   REMEDIES  .     727 


A  TEXT  BOOK  OF  PHARMACOLOGY. 


INTRODUCTION. 

PHARMACOLOGY  is  the  study  of  the  changes  induced  in  living  organ- 
isms by  the  administration  in  a  state  of  minute  division  of  such  un- 
organized substances  as  do  not  act  merely  as  foods.  Many  of  the  best 
known  of  these  substances  are  used  to  counteract  the  effects  of  disease, 
or  to  reinforce  the  tissues  in  their  struggle  to  maintain  their  functions, 
when  these  are  rendered  abnormal.  These  substances  are  known 'as 
drugs,  and  the  art  of  applying  drugs  in  disease,  is  Therapeutics.  Other 
substances  are  of  little  or  no  value  in  disease,  but  are  of  importance 
because  they  act  as  poisons,  that  is,  cause  dangerous  or  fatal  symptoms 
in  man  or  animals,  when  they  are  ingested  in  quantity.  The  practical 
study  of  the  effects  of  these  poisons  in  man  —  the  diagnosis  and  the 
treatment  of  poisoning,  and  the  methods  of  detecting  the  poison  —  is 
termed  Toxicology.  But  the  explanation  of  the  symptoms  induced  by 
chemical  substances,  and  their  study,  as  apart  from  their  practical  ap- 
plications, belong  to  the  field  of  pharmacology,  which  includes  not  only 
the  effects  of  drugs  and  poisons,  but  those  of  any  substance  which 
induces  changes  in  the  living  organism,  whether  those  changes  are  of 
benefit  to  it,  injurious,  or  quite  indifferent.1 

The  substances  must,  of  course,  conform  to  the  requirements  of  the  defini- 
tion. Thus,  a  needle  introduced  into  the  tissues  induces  effects  which  are 
outside  the  field  of  pharmacological  investigation,  because  it  is  not  in  a  state 
of  minute  division.  But  the  iron  of  the  needle  may  be  reduced  to  a  fine 
powder  and  induce  changes  in  the  body  which  are  then  the  legitimate  subject 
of  research.  Similarly  the  drug  must  be  introduced  from  without,  for  many 
active  agents  are  formed  within  the  body,  but  their  study  belongs  rather  to 
the  departments  of  physiology  and  pathology  ;  and  the  effects  of  organized 
bodies  introduced  from  without  are  now  studied  under  bacteriology.  Phar- 
macology is  really  a  department  of  biology,  very  closely  related  to  the  other 
sciences  included  by  that  term.  Thus,  as  physiology  is  the  study  of  the  life 
of  the  normal  organism,  pharmacology  is  the  study  of  the  organism  rendered 
abnormal  by  drugs,  while  in  pathology  the  phenomena  of  life  under  disease 
are  examined.  All  three  subjects  may  be  pursued  without  reference  to  the 
practical  needs  of  medicine,  and  all  three  are  closely  interconnected  and 
mutually  dependent,  for,  in  many  instances,  the  normal  condition  of  an 
organ  can  be  recognized  only  by  considering  the  results  of  its  destruction 
by  disease  (pathology),  or  of  its  paralysis  or  stimulation  by  chemical  agents 

1  It  is  quite  impossible  to  distinguish  between  drugs  and  poisons.     Almost  all  reme- 
dies given  in  excess  cause  dangerous  or  fatal  symptoms,  while  many  poisons  are  valuable 
remedies  in  small  doses.     Some  bodies  may  in  fact  be  remedies,  foods,  or  poisons  accord- 
ing to  the  quantity  ingested  and  the  method  of  application. 
2  17 


18  INTRODUCTION. 

(pharmacology).  Similarly,  many  of  the  features  of  disease  are  now  rec- 
ognized to  be  due  to  the  presence  of  unorganized  poisons  formed  in  and  by 
the  tissues,  and  it  accordingly  becomes  difficult  to  accurately  define  the 
limits  of  pathology  and  pharmacology.  Thus,  the  toxines  formed  by  microbes 
resemble  in  their  action  some  of  the  ordinary  drugs  or  poisons,  and  might  be 
considered  along  with  these.  But  the  study  of  these  toxines  is  so  closely 
bound  up  with  that  of  the  microbes  from  which  they  originate,  that  it  has 
been  thought  better  to  leave  them  to  be  treated  by  special  text-books  on  bac- 
teriology. For  a  similar  reason  the  antitoxines,  which  play  so  prominent  a 
role  in  modern  therapeutics,  may  be  excluded  from  treatises  on  pharmacol- 
ogy, for  the  present  at  any  rate. 

Even  when  these  limitations  are  accepted,  pharmacology  has  an 
enormous  field  to  cover,  and  one  which  has  been  only  very  partially  ex- 
plored at  the  present  day,  in  spite  of  the  unremitting  industry  of  many 
investigators.  But  a  small  part  of  the  subject  has  been  sufficiently 
developed  to  admit  of  text-book  treatment,  that  namely,  which  is  con- 
cerned with  drugs  used  in  therapeutics  and  with  the  commoner  poisons. 
The  slow  advance  of  pharmacology  is  partly  due  to  its  position  midway 
between  the  biological  sciences  and  practical  therapeutics,  for  while  the 
biologist  confounds  it  with  clinical  study,  the  clinician  regards  it  as  an 
experimental  science.  Its  relation  to  biology  has  already  been  men- 
tioned and  its  relation  to  practical  therapeutics  is  no  less  close,  for  the 
effects  of  drugs  in  disease  are  as  much  a  part  of  pharmacology  as  is  their 
action  in  the  nonnal  organism.  The  aim's  of  the  pharmacologist  and  the 
clinician  are  not  identical,  however.  The  former  seeks  to  solve  the 
problem  how  the  drug  acts  in  a  given  case,  while  the  primary  object  of 
the  latter  is  to  remedy  the  condition  by  any  means  in  his  power.  Thus, 
in  a  case  of  heart  weakness,  the  clinician  prescribes  some  remedy  which 
he  has  found  of  benefit  in  other  similar  cases,  and  regards  only  as  of 
secondary  interest  the  question  which  to  the  pharmacologist  is  the 
absorbing  one,  namely,  whether  the  drug  acts  on  the  heart  directly  or 
through  some  other  organ.  Of  course  the  results  are  of  mutual  ad- 
vantage, for  the  physician  supplies  the  experimental  investigator  with 
new  facts  and  with  new  fields  of  inquiry,  while  the  latter  may  indicate 
more  exactly  the  conditions  in  which  the  drug  is  likely  to  be  of  benefit 
in  the  future  by  defining  the  method  in  which  it  acts.  It  is,  therefore, 
much  to  be  regretted  that  differences  of  opinion  so  often  arise  between 
these  two  classes  of  observers,  for  these  can  only  retard  the  progress  of 
both  the  science  and  the  practical  art.  Doubtless  there  are  often  faults 
on  both  sides.  The  scientist  sometimes  insists  too  strongly  on  induc- 
tions drawn  from  a  limited  number  of  animal  experiments,  and  refuses 
to  admit  results  which  have  been  obtained  in  thousands  of  cases  of  dis- 
ease by  competent  observers.  On  the  other  hand,  the  therapeutist  often 
lays  too  little  weight  on  the  general  principles  governing  the  interaction 
of  the  drug  and  the  organism.  Both  often  exceed  the  limits  of  their 
provinces,  the  scientist  in  refusing  to  admit  effects  of  which  he  has  per- 
force but  a  small  experience,  the  clinician  in  attempting  to  refute  de- 
ductions founded  on  experiments  which  he  has  no  opportunity  of  per- 
forming. An  example  may  render  the  relation  of  these  allied  subjects 


PHAEMA  COLOG  Y.  19 

clearer,  and  one  has  been  recently  offered  in  the  discussion  regarding 
the  effects  of  iron.  This  metal  has  been  used  for  many  years  in  a  form 
of  anaemia,  and  its  curative  properties  are  attested  by  many  thousands 
of  cases  and  by  whole  generations  of  practical  physicians.  A  phar- 
macologist, therefore,  exceeds  his  province  when  he  expresses  doubt 
regarding  this  clinical  fact  simply  because  he  is  unable  to  explain  it, 
but  he  is  within  his  rights  in  discussing  the  means  by  which  iron  acts 
as  a  remedy.  The  clinician,  on  the  other  hand,  enters  on  a  pharma- 
cological question  when  he  attempts  to  determine  whether  iron  acts  by 
absorption  or  by  its  presence  in  the  bowel,  and  must  base  his  argu- 
ments on  scientific  experiment  and  not  on  his  clinical  experience  of  the 
curative  effects  of  the  metal.  Fortunately  for  the  progress  of  medicine 
and  pharmacology,  the  scientific  clinician  is  imbued  with  the  desire  to 
ascertain  the  methods  in  which  drugs  act  as  well  as  to  cure  disease,  and 
thus  unites  clinical  observation  with  pharmacological  research.  It  is 
to  be  anticipated  that  the  results  of  the  practical  physician  and  of  the 
experimental  investigator  will  come  into  more  complete  accord  as 
more  exact  methods  of  clinical  research  are  used  by  the  former,  and 
a  wider  laboratory  experience  is  attained  by  the  latter.  But  both 
methods  are  necessary  to  the  complete  knowledge  of  the  action  of  a 
drug.  Animal  experiment  cannot  be  dispensed  with,  for  only  thus 
can  the  action  of  drugs  be  ascertained  in  detail  and  expeditiously,  and 
at  the  present  time,  when  a  new  remedy  appears  almost  every  week,  it 
is  impossible  to  await  the  verdict  of  the  clinics  to  separate  the  useful 
from  the  worthless,  even  if  it  were  permissible  to  apply  to  the  human 
subject  drugs  of  unknown  action  and  potency. 

Pharmacology  is  one  of  the  most  recent  developments  of  medical  and 
biological  science.  It  is  true  that  from  the  earliest  times  attempts  have 
been  made  to  explain  the  effects  of  drugs  on  the  then  prevailing  theo- 
ries of  pathology,  but  the  objective  study  of  the  action  of  drugs  on  the 
organism  has  been  a  development  of  the  nineteenth  century,  or  it  might 
almost  be  said,  of  the  second  half  of  it.  During  this  period  the  same 
methods  of  research  have  been  adopted  as  had  earlier  proved  so  fruitful 
in  physiology  and  pathology,  and  with  equally  happy  results.  The 
study  of  drugs  was  termed  Materia  Medica  up  to  this  time,  and  com- 
prised an  examination  of  their  botanical  and  chemical  properties  along 
with  some  account  of  the  diseases  in  which  they  had  proved  of  value. 
This  descriptive  rather  than  experimental  study  has  been  continued 
under  the  name  of  Pharmacognosy,  but  is  now  pursued  by  pharmacists 
chiefly.  Undoubtedly  the  student  of  medicine  ought  to  know  those 
characters  of  drugs  which  are  of  importance  as  modifying  their  action 
and  application,  but  it  is  undesirable  that  his  valuable  time  should  be 
occupied  in  the  detailed  description  of  crude  substances,  which  he  may 
probably  never  have  an  opportunity  of  seeing  in  his  future  practice. 

Another  subject  which  now  occupies  a  much  less  prominent  position 
in  medical  study  than  formerly,  is  Pharmacy,  or  the  art  of  preparing 
drugs  for  therapeutic  use.  Some  general  knowledge  of  the  methods 
used  is  no  doubt  indispensable  to  the  educated  physician,  but  the  de- 


20  INTRODUCTION. 

tails  may  be  left  to  the  pharmacist.  Pharmacy  will  probably  occupy  a 
still  more  subordinate  position  in  medical  education  as  the  tendency 
to  include  only  one  or  two  drugs  in  a  prescription  becomes  more  wide- 
spread. As  long  as  a  dozen  or  more  components  went  to  make  one 
mixture,  it  was  of  importance  to  know  their  solubility  and  their  inter- 
actions, but  with  the  decay  of  the  complex  prescription  the  study  of 
pharmacy  by  medical  students  has  certainly  become  less  imperative. 

MODE  OF  ACTION  OF  DRUGS.     STIMULATION, 
DEPRESSION  AND  IRRITATION. 

A  small  number  of  drugs  affect  the  organism  only  through  their  phy- 
sical properties,  as  when  an  inert  oily  body  is  applied  to  an  abraded 
surface  and  promotes  its  healing  by  protecting  it  from  irritation  and 
from  the  evaporation  of  fluid,  or  when  common  salt  absorbed  into  the 
blood  changes  its  osmotic  tension,  and  thus  alters  the  distribution  of 
fluids  in  the  tissues. 

But  the  great  majority  of  drugs  act  through  their  chemical  affinity 
for  certain  forms  of  living  matter.  They  probably  form  temporary 
combinations  with  some  forms  of  protoplasm,  and  alter  the  function  of 
all  cells, which  contain  these  forms.  At  least  this  is  the  only  explana- 
tion of  their  affecting  certain  organs  while  others  escape  their  influ- 
ence. To  take  an  example,  the  cells  of  the  spinal  cord  normally  receive 
sensory  impressions  from  the  exterior  and  send  out  motor  impulses. 
But  under  strychnine  the  motor  impulses  are  much  more  violent  than 
usual,  and  this  may  be  expressed  by  saying  that  the  combination  of 
strychnine  and  cord  protoplasm  functions  more  powerfully  than  unal- 
tered cord  protoplasm.  The  activity  is  changed,  however,  only  in  de- 
gree and  not  in  kind ;  the  reflex  movement  may  be  more  powerful  or 
less  powerful  than  normally,  but  it  remains  a  reflex  movement  and  can- 
not under  any  circumstances  partake  of  the  nature  of  a  voluntary  move- 
ment. In  other  words,  the  action  of  drugs  is  quantitative  and  not 
qualitative,  the  activity  of  living  matter  may  be  changed,  but  the  form 
which  the  activity  assumes  is  unchangeable. 

In  recent  years  much  attention  has  been  paid  to  a  series  of  natural 
phenomena  occurring  in  the  border-land  between  physics  and  chem- 
istry and  the  application  of  the  results  of  "  physical  chemistry "  to 
pharmacology  has  proved  of  great  value  already  and  promises  to  eluci- 
date in  the  future  many  problems  which  have  hitherto  been  unap- 
proachable. Examples  of  such  applications  will  be  met  in  the  Meyer- 
Overton  theory  of  narcosis  and  in  the  chapters  on  salt  action.  The 
tendency  of  study  in  this  direction  is  to  reduce  the  class  of  reactions 
which  have  hitherto  been  ascribed  to  special  chemical  affinity  between 
drugs  and  protoplasm  and  to  attribute  many  of  the  changes  induced  by 
drugs  to  the  physical  structure  of  the  living  cell  rather  than  to  its 
chemical  constitution. 

Drugs  which  increase  the  activity  of  any  organ  or  function  are  said 
to  stimulate  it,  while  those  which  lessen  the  activity  are  said  to  depress 


MODE  OF  ACTION  OF  DRUGS.  21 

it.  Another  condition  induced  by  drugs  is  irritation,  for  although  this 
term  is  often  applied  loosely  as  a  synonym  for  stimulation,  the  two 
conditions  are  not  identical.  Stimulation  is  properly  used  to  indicate 
an  increase  in  the  specialized  function  of  a  cell,  producing,  for  instance, 
in  the  spinal  cord  an  increase  in  the  reflex  excitability.  Irritation, 
on  the  other  hand,  is  used  rather  in  reference  to  the  changes  in  the 
conditions  common  to  all  forms  of  living  matter,  that  is,  it  indicates  a 
change  in  the  nutrition  and  growth  of  the  cell,  rather  than  in  the 
specialized  functions.  Irritation  may  thus  be  induced  in  all  kinds 
of  tissues  and  is  the  commonest  change  caused  by  drugs  in  the  less 
differentiated  forms  such  as  the  connective  tissues  and  ordinary 
epithelia ;  while  stimulation  is  met  with  in  the  more  highly  specialized 
cells,  such  as  those  of  the  heart,  nervous  system,  or  secretory  glands. 
In  many  instances  the  irritant  action  of  drugs  may  be  explained  by 
their  known  reactions  with  the  proteids  of  the  cell ;  for  example,  sub- 
stances which  dissolve  proteids,  or  precipitate  them,  or  withdraw  fluid 
from  them,  all  tend  to  cause  irritation  when  they  are  applied  to  living 
tissues.  In  other  cases  irritation  appears  to  be  induced  through  some 
chemical  action  the  nature  of  which  is  quite  unknown. 

When  stimulation  is  prolonged  or  excessive,  the  protoplasm  gener- 
ally becomes  depressed  and  finally  loses  its  activity  entirely  (paralysis). 
Some  authorities  have  asserted  that  depression  is  invariably  preceded 
by  stimulation,  and  that  stimulation  sufficiently  prolonged  invariably 
leads  to  depression  and  paralysis.  Both  statements  are  too  absolute, 
although  they  are  true  in  the  great  majority  of  cases.  For  example, 
the  action  of  atropine  on  the  terminations  of  the  cardiac  inhibitory 
nerves  is  purely  depressant.  Even  the  most  minute  quantities  of  this 
alkaloid  never  increase  the  activity  of  these  terminations,  for  if  a  quan- 
tity too  small  to  paralyze  them  is  ingested,  it  has  apparently  no  effects 
whatever,  and  as  the  dose  is  increased,  the  first  effect  is  paralysis. 

Depression,  whether  induced  directly,  or  following  on  stimulation, 
has  been  shown  in  several  instances  to  resemble  the  fatigue  induced  by 
the  prolonged  exercise  of  the  normal  organ,  and  it  is  probably  true  that 
depression  and  fatigue  are,  in  all  instances,  identical  in  appearance,  al- 
though not  necessarily  identical  in  cause.  For  example,  the  phenom- 
ena of  fatigue  of  the  terminations  of  the  motor  nerves  in  muscle  re- 
semble exactly  those  induced  by  curara,  but  in  the  former  the  cause 
may  be  that  the  conducting  substance  of  the  nerve  ends  has  been  used 
up  by  the  repeated  passage  of  impulses,  while  in  the  latter  the  conduct- 
ing substance  is  so  changed  that  it  becomes  incapable  of  transmitting 
stimuli  to  the  muscles.  The  final  result  is,  of  course,  the  same  ;  there 
being  no  available  conducting  substance,  impulses  fail  to  reach  the 
muscle.  But  the  fatigued  terminations  rapidly  recover,  as  conducting 
substance  is  reformed,  while  the  curarized  recover  only  when  the  poison 
is  eliminated. 

In  most  cases  an  excessive  dose  of  a  stimulating  poison  leads  to  de- 
pression and  paralysis.  The  cell  becomes  functionally  dead,  but  if  the 
failure  of  its  function  does  not  involve  the  death  of  the  organism,  it 


22  INTE  OD  UCTION. 

may  recover  and  reassume  its  ordinary  function  as  if  no  stage  of  inac- 
tivity had  intervened.  Excessive  irritation,  on  the  other  hand,  leads 
to  actual  death  and  disintegration,  from  which  there  is  no  recovery. 
For  example,  the  cells  of  the  spinal  cord  are  first  stimulated,  and  later 
paralyzed  by  a  large  dose  of  strychnine,  but  this  is  not  fatal  to  cold- 
blooded animals,  and  after  a  few  days  the  spinal  cord  regains  its  nor- 
mal function,  as  the  poison  is  eliminated.  On  the  other  hand,  the  in- 
jection of  an  irritant  into  the  subcutaneous  tissues  causes  dilatation  of 
the  vessels,  effusion  of  fluid,  and  increased  growth  and  rapid  division 
of  the  cells.  If  only  a  small  quantity  be  injected,  this  condition  is 
recovered  from,  although  it  generally  leaves  evidence  of  its  presence  in 
the  form  of  an  increase  in  the  fibrous  tissue.  But  if  the  irritation  be 
intense,  the  cells  undergo  degeneration  and  die,  and  an  abscess  is 
formed.  The  cells  thus  destroyed  can  never  recover  as  the  paralyzed 
ones  do.  They  are  either  absorbed,  or  removed  by  the  opening  of  the 
abscess,  and  their  room  is  filled  by  the  overgrowth  of  the  neighboring 
tissues. 


ELECTIVE  AFFINITY  OF  DRUGS.     PROTOPLASM  POISONS. 

Most  drugs  have  an  elective  affinity  for  certain  definite  tissues. 
Thus,  some  attack  the  heart  only,  others  the  central  nervous  system 
and  others  the  terminations  of  the  motor  nerves  in  muscle.  Among 
the  cardiac  poisons  again,  some  act  on  the  ventricle,  others  on  the 
auricle,  and  among  the  poisons  of  the  central  nervous  system,  some  act 
primarily  on  the  cortex,  others  on  the  medulla  oblongata  and  others 
on  the  spinal  cord.  This  elective  affinity  is  not  merely  a  question  of 
degree,  as  is  sometimes  stated,  for  a  drug  which  has  a  powerful  action 
on  the  brain,  may  have  no  effect  on  the  heart  except  when  administered 
in  such  quantities  as  alter  the  physical  characters  of  the  blood.  A 
drug  may  even  alter  different  structures  in  diametrically  opposite  direc- 
tions. Thus,  atropine  depresses  certain  nerve  terminations,  but  stimu- 
lates the  brain,  and  curara,  which  paralyzes  the  peripheral  terminations 
of  the  motor  nerves,  stimulates  the  spinal  cord.  In  some  instances 
the  immunity  of  a  cell  to  the  action  of  a  drug  may  perhaps  be  explained 
by  the  latter  failing  to  penetrate  into  its  interior,  but  this  is  not  true  in 
the  great  majority  of  cases. 

The  fields  of  activity  of  different  drugs  vary  greatly  in  extent.  One 
may  comprise  only  the  terminations  of  the  secretory  fibres  in  the  sweat 
glands  (agaricin),  while  another,  which  affects  these  in  the  same  way, 
may  involve  many  other  terminations  in  its  action  (atropine).  Most 
poisons,  however,  while  acting  on  a  certain  narrow  area  in  small  doses, 
extend  the  limits  of  their  activity  when  larger  quantities  are  ingested. 
Thus,  a  poison  which  acts  in  small  doses  on  the  medulla  oblongata 
only,  may,  when  exhibited  in  larger  quantities,  involve  the  spinal  cord 
and  the  brain,  and  in  still  greater  concentration  may  affect  the  heart 
and  other  organs.  No  poison  is  known  that  acts  equally  on  all  organs 
and  tissues,  but  those  which  have  a  wide  field  of  operation  are  often 


REMOTE,   LOCAL,   AND   GENERAL  ACTION.  23 

known  as  protoplasm  poisons.  These  paralyze  any  form  of  living  mat- 
ter when  they  are  brought  in  contact  with  it  in  sufficient  quantity,  but 
if  they  are  injected  into  the  blood  and  thus  distributed  equally  through- 
out the  body,  they  invariably  select  some  special  organ  as  the  chief 
seat  of  their  activity.  This  is  exactly  parallel  to  the  behavior  of  chem- 
ical agents  in  the  laboratory.  For  example,  acetate  of  lead  added  to 
a  solution  of  a  chloride,  or  of  a  sulphate,  precipitates  it,  but  added  to 
a  mixture  of  the  two,  throws  down  more  of  the  sulphate  than  of  the 
chloride.  Nitrate  of  silver,  on  the  other  hand,  precipitates  the  chloride 
only.  Acetate  of  lead  may  be  compared  to  the  protoplasm  poisons, 
nitrate  of  silver  to  those  with  a  less  extensive  field  of  action.  As  proto- 
plasm poisons  affect  a  large  number  of  different  forms  of  living  matter 
it  follows  that  they  alter  the  nutrition  rather  than  specialized  functions. 
Many  of  them  cause  irritation  ;  others  are  used  to  destroy  or  retard  the 
growth  of  microbes  and  are  known  as  disinfectants  or  antiseptics. 

REMOTE,   LOCAL,   AND   GENERAL   ACTION. 

Drugs  change  directly  only  those  organs  and  tissues  with  which  they 
come  into  immediate  contact.  But  the  alteration  of  one  part  of  the 
organism  very  often  entails  that  of  another  to  which  the  drug  may  not 
have  access,  or  for  which  it  has  no  special  affinity,  because  impulses  are 
transmitted  through  the  nerves,  or  changes  are  induced  in  the  circula- 
tion and  nutrition.  Thus  irritation  of  the  skin  may  alter  the  rate  of 
the  pulse  by  impressions  being  transmitted  by  the  cutaneous  nerves 
and  reflected  along  the  inhibitory  nerves  of  the  heart.  Similarly  a 
poison  that  weakens  the  heart  may  induce  disorder  of  the  respiration, 
from  the  circulation  being  deficient  in  the  medulla  oblongata ;  and 
depression  of  the  brain  may  lessen  the  oxidation  in  the  muscles,  because 
it  leads  to  lessened  movement.  These  secondary  changes,  which  are 
not  due  to  the  direct  action  of  the  drug  on  the  organs  concerned,  are 
known  as  remote  or  indirect  effects. 

The  local  action  of  a  drug  is  that  induced  at  the  point  of  application 
before  it  enters  the  circulation,  the  general  or  systemic  action  is  that  due 
to  its  elective  affinity  for  certain  organs  to  which  it  is  carried  by  the 
blood.  The  local  effects  are  very  often  entirely  different  in  nature 
from  the  general  action,  for  a  drug  may  act  as  an  irritant  at  the  point 
of  application  and  as  a  depressant  to  the  brain  when  it  is  carried  to  it 
in  the  blood.  Local  effects  may  be  induced  wherever  the  drug  can  be 
applied — in  the  skin,  the  alimentary  tract,  the  respiratory  passages,  and 
the  other  mucous  membranes.  They  also  occur  in  the  subcutaneous 
tissues  when  the  poison  is  injected  hypodermically,  and  in  any  of  the 
deeper  organs  and  tissues  which  can  be  reached  by  the  needle  of  the 
syringe.  Local  remedies  may  cause  irritation,  or  may  protect  the  sur- 
face from  irritation,  may  depress  the  sensory  end-organs  and  cause 
local  anaesthesia,  or  lessen  secretion,  or  alter  the  functions  at  the  point 
of  application  in  many  other  ways.  They  may  also  have  remote  effects, 
as  has  been  mentioned.  Many  drugs  have  only  a  local  action,  because 


24  INTRODUCTION. 

they  are  not  absorbed,  are  absorbed  in  inactive  forms,  or  are  excreted 
or  deposited  as  rapidly  as  they  pass  into  the  circulation,  so  that  enough 
is  not  present  in  the  blood  at  any  one  time  to  induce  general  effects. 
On  the  other  hand,  many  powerful  poisons  have  little  or  no  effect  at  the 
point  of  application,  but  possess  an  elective  affinity  only  for  some 
organ  to  which  they  are  carried  by  the  circulation. 

THE   RELATION  BETWEEN   CHEMICAL   COMPOSITION 
AND  PHARMACOLOGICAL  ACTION. 

As  the  effect  of  drugs  on  living  matter  is  conceived  to  be  due  to  a 
chemical  reaction  between  them,  it  might  be  inferred  that  those  drugs 
which  present  a  close  resemblance  in  their  chemical  properties  and  com- 
position must  induce  similar  changes  in  the  organism.  And  this  is  true 
as  a  general  statement,  although  the  relation  existing  between  chemical 
constitution  and  pharmacological  action  can  be  followed  only  a  short 
distance  as  yet.  For  example,  so  many  members  of  the  methane  series 
of  chemistry  depress  the  central  nervous  system  that  this  may  be  re- 
garded as  a  general  property  of  these  bodies,  just  as  they  possess  certain 
general  chemical  reactions,  which  distinguish  them  from  the  members 
of  other  chemical  series.  In  the  same  way,  the  heavy  metals  resemble 
each  other  in  their  general  effects  on  the  organism,  just  as  they  react 
similarly  to  some  chemical  tests.  But  whenever  an  attempt  is  made  to 
follow  this  relation  in  detail,  the  analogy  breaks  down,  because  factors 
which  it  is  impossible  to  deduce  from  the  chemical  constitution,  make 
themselves  felt.  Exactly  the  same  thing  occurs  in  chemistry ;  for 
example,  the  heavy  metals  resemble  each  other  in  so  many  respects  that 
it  might  be  inferred  that  the  sulphides  would  be  of  the  same  color,  or 
that  the  chlorides  would  be  equally  soluble  in  water,  but  experiment 
shows  that  this  is  not  the  case.  In  the  same  way  they  resemble  each 
other  in  many  points  in  their  effects  in  the  organism,  but  it  cannot  be 
inferred  from  this  that  they  will  have  the  same  effect  on  any  given 
organ  or  in  any  given  respect.  A  simple  example  of  the  very  differ- 
ent effects  in  the  organism  of  drugs  which  are  closely  related  chemically, 
is  offered  by  the  action  of  the  simpler  members  of  the  acetic  acid  series 
on  the  sense  of  smell.  For  formic,  acetic,  proprionic,  butyric  and 
valerianic  acids  can  be  easily  distinguished  by  their  odors,  that  is,  they 
act  differently  on  the  terminations  of  the  olfactory  nerves,  yet  they 
form  a  homologous  series  of  as  closely  related  members  as  any  chemical 
series  can  offer.  They  present  certain  differences  in  their  chemical 
reactions,  of  course ;  for  example  they  vary  considerably  in  the  solu- 
bility of  the  salts  they  form  with  barium  and  calcium,  and  it  is  im- 
possible to  explain,  or  to  anticipate  these  variations  from  any  consider- 
ation of  their  chemical  constitution.  If  then  their  reactions  with  such 
simple  and  familiar  bodies  as  calcium  and  barium  cannot  be  anticipated, 
it  would  seem  futile  to  attempt  to  foretell  their  behavior  towards  the 
infinitely  more  complex  and  less  known  protoplasm  of  the  nerve  ter- 
minations. 


CONDITIONS  MODIFYING   THE  EFFECTS  OF  DRUGS.  25 

A  great  deal  of  time  and  energy  has  been  devoted  to  an  attempt  to 
bring  the  effects  in  the  organism  of  certain  metals  (notably  the  alkalies) 
into  relation  with  their  atomic  weights,  their  valency,  electrical  charges, 
and  other  properties,  but  no  results  are  to  be  expected  from  these 
researches,  so  long  as  the  ordinary  chemical  reactions  of  these  bodies 
can  only  be  formulated  to  a  limited  extent  and  imperfectly  from  such 
considerations.  In  particular,  it  seems  of  little  interest  to  determine 
their  exact  relative  toxicity,  since  there  is  no  question  that  they  do  not 
all  act  on  the  same  organs ;  and  if  one  act  on  the  brain  and  another  on  the 
heart,  one  by  its  specific  affinity  for  an  organ  and  another  by  inducing 
physical  changes  in  the  fluids  of  the  body,  these  differences  are  sufficient 
to  nullify  any  relation  which  they  may  bear  to  each  other  in  regard  to 
the  exact  fatal  dose.  As  has  been  stated,  it  may  be  inferred  with  some 
probability  that  any  substance  belonging  to  certain  wide  chemical  groups 
will  induce  symptoms  in  the  organism  resembling  in  general  characters 
those  of  the  other  members,  provided  always  that  it  does  not  contain  some 
radicle  which  renders  it  inactive,  or  gives  it  a  more  powerful  action  in 
some  other  direction.  But  the  details  of  its  action  can  be  ascertained 
only  by  actual  experiment,  exactly  as  the  details  of  its  chemical  be- 
havior can  be  known  only  by  performing  the  necessary  reactions ;  and 
as  there  is  no  prospect  of  explaining  the  latter  from  its  constitution  at 
the  present  time,  there  is  still  less  hope  that  much  advance  will  be 
made  in  the  near  future  in  formulating  the  laws  governing  the  details 
of  its  pharmacological  effects. 

CONDITIONS  MODIFYING  THE  EFFECTS  OF  DRUGS. 

The  effects  of  drugs  on  the  living  organism  are  subject  to  some  modi- 
fications in  certain  individuals,  and  under  some  conditions,  which  it 
is  of  importance  that  the  physician  should  recognize,  as  the  dose  has  to 
be  altered  when  they  are  present.  One  of  these  is  the  Size  and  Weight. 
If  the  same  amount  of  a  poison  be  distributed  through  the  tissues  of 
a  large  individual  as  of  a  small  one,  less  is  contained  in  any  given  organ 
of  the  former  and  less  effect  is  therefore  observed.  This  has  been 
ascertained  chiefly  in  animal  experiment,  in  which  the  effects  of 
drugs  can  be  estimated  much  more  exactly  than  in  man,  but  it  un- 
doubtedly holds  good  for  human  beings  also.  Very  large  individ- 
uals, then,  require  a  somewhat  larger  dose  than  ordinary  persons, 
while  in  treating  individuals  of  small  stature,  the  dose  has  to  be 
reduced. 

The  Age  of  the  patient  has  also  to  be  taken  into  account  in  prescrib- 
ing. Children  ought  to  receive  much  smaller  doses  than  adults.  The 
more  powerful  action  of  drugs  in  children  is  due  in  part  to  their  smaller 
size,  in  part  to  the  more  active  growth  of  certain  tissues  and  to  the  less 
complete  development  of  others,  such  as  the  central  nervous  system. 
The  dose  for  a  child  is  generally  calculated  according  to  Young's 
formula,  in  which  a  fraction  obtained  by  dividing  the  age  by  the  age  + 
12,  is  taken  as  the  proportion  of  the  adult  dose  required.  Thus  for  a 


26  INTRODUCTION. 

child  of  four  years,  the  dose  would  be  f  ^ fs  =  )  i  of  the  adult  dose, 

for  one  of  one  year  (  ^ — — i-^  =  j  ^  of  the  adult  dose.     According  to 

another  less  used  formula,  the  dose  for  a  child  is  ascertained  by  divid- 
ing the  adult  dose  by  20,  and  multiplying  the  result  by  the  age. 
Brunton  suggests  dividing  the  dose  by  25  and  multiplying  the  result 
by  the  age  at  the  next  birthday.  These  formulae  are  not,  however,  inva- 
riably safe  guides  to  follow  in  prescribing.  For  example,  the  narcotics, 
particularly  opium  and  its  preparations,  must  be  given  during  the  first 
years  of  life  in  much  smaller  quantities  than  are  indicated  by  Young's 
rule,  while  alcohol  may  be  administered  in  comparatively  large  doses. 

The  usual  dose  advised  has  to  be  modified  for  children  then,  and 
may  be  taken  as  that  suitable  from  20-60  years.  After  this  age  is 
passed,  it  is  again  reduced  somewhat,  so  that  from  70-80  about  f  of 
the  adult  dose  is  advised,  and  after  85  it  may  be  reduced  to  J.  There 
are  exceptions  to  this  rule  also,  large  doses  of  the  purgatives,  for  ex- 
ample, being  often  necessary  in  old  people. 

Sex. — Women  generally  require  somewhat  smaller  doses  than  men, 
because  of  their  smaller  size,  and  it  is  often  stated,  because  their  tissues 
react  more  strongly  to  some  drugs,  though  this  has  not  yet  been  satis- 
factorily established. 

Temporary  conditions  also  influence  the  activity  of  drugs.  Thus 
after  a  mealy  a  poison  is  absorbed  more  slowly  from  the  stomach  than 
when  it  is  taken  fasting,  and  any  local  irritant  action  is  also  less 
marked,  because  the  drug  is  diluted  by  the  contents  of  the  stomach. 
Irritation  of  the  stomach  and  intestine  may  also  modify  the  effects  of 
drugs ;  thus  in  some  forms  of  dyspepsia  the  absorption  is  slower  than 
usual  and  little  effect  may  be  induced  by  the  ordinary  dose,  while  irri- 
tant drugs  naturally  cause  more  disturbance  of  the  digestion  in  these 
cases.  On  the  other  hand,  a  slight  congestion  of  the  stomach  and  bowel 
tends  to  promote  absorption,  and  it  has  been  found  that  more  of  a 
heavy  metal  is  absorbed  when  it  causes  some  destruction  of  the  mucous 
membrane  than  when  it  is  given  in  smaller  quantities.  Vomiting 
and  diarrhoea,  of  course,  tend  to  lessen  the  action  of  drugs  by  re- 
moving them  rapidly  from  the  alimentary  canal. 

During  pregnancy,  purgatives  have  to  be  used  with  great  care,  be- 
cause they  induce  congestion  of  the  pelvis,  and  may  lead  to  abortion. 
Drugs  acting  on  the  uterus,  or  inducing  a  marked  fall  of  blood  pres- 
sure, are  to  be  avoided  because  the  former  may  cause  the  evacuation  of 
the  uterine  contents,  while  the  latter  may  lead  to  asphyxia  of  the  foetus. 
Many  drugs  pass  from  the  mother  to  the  child,  and  this  is  to  be  borne 
in  mind,  as  quantities  which  are  insufficient  to  poison  the  former  may 
have  more  serious  effects  on  the  latter.  During  lactation,  it  is  impor- 
tant to  remember  that  active  bodies  may  be  excreted  in  the  milk,  and 
may  either  act  on  the  child  or  render  the  milk  distasteful  to  it.  In 
menstruation,  purgatives  are  to  be  avoided,  as  they  tend  to  increase 


CONDITIONS  MODIFYING  THE  EFFECTS  OF  DRUGS.  27 

the  flow,  and  all  very  active  drugs  are  to  be  used  with  care  or  aban- 
doned temporarily. 

The  Time  of  Administration  has  also  some  influence  on  the  effects  of 
drugs.  The  body  is  generally  more  resistant  in  the  morning  than  in 
the  evening,  especially  in  the  case  of  narcotic  drugs ;  thus  a  dose  of  a 
soporific  which  may  have  little  or  no  effect  in  the  early  hours,  induces 
sound  sleep  when  given  in  the  evening,  because  the  brain  is  already 
fatigued  and  depressed. 

Idiosyncrasy  is  used  to  denote  an  unusual  effect  for  which  no  expla- 
nation can  be  found.  Some  persons  react  more  readily  than  usual  to 
the  ordinary  dose,  while  in  other  instances  a  much  larger  quantity  can 
be  taken  without  any  effect.  Others,  again,  show  symptoms  which  are 
entirely  different  from,  and  which  may,  in  fact,  be  diametrically  opposite 
to  those  ordinarily  observed.  These  idiosyncrasies  are  naturally  more 
frequently  seen,  and  are  better  known  when  they  arise  from  widely 
used  drugs.  Thus  the  modern  antipyretics  have  so  often  induced  ab- 
normal symptoms  that  these  are  well  known,  but  it  is  not  improbable 
that  if  other  drugs  had  been  used,  or  rather  abused,  to  the  same  extent, 
they  would  be  found  to  induce  unusual  reactions  in  an  equally  large 
number  of  individuals.  An  idiosyncrasy,  as  has  been  said,  cannot  be 
explained  in  the  present  state  of  knowledge,  but  some  conditions  which 
have  been  termed  idiosyncrasies  are  probably  due  to  abnormally  rapid, 
or  to  retarded  absorption  or  excretion.  Idiosyncrasies  are  not  con- 
fined to  human  beings,  for  not  infrequently  one  animal  reacts  quite 
differently  from  others  of  the  same  species. 

As  has  been  mentioned,  one  form  of  idiosyncrasy  consists  in  the  fail- 
ure of  the  individual  to  react  to  the  ordinary  dose  of  a  drug.  This  is 
known  as  Tolerance,  and  this  particular  form  of  idiosyncrasy  may  be 
termed  congenital  tolerance.  Certain  species  of  animals  tolerate  quan- 
tities of  drugs  which  would  be  fatal  to  others  of  the  same  size.  In 
fact,  so  frequently  is  this  the  case  that  it  is  impossible  to  determine  the 
fatal  dose  of  any  drug  on  an  animal  from  experiments  performed  upon 
others  of  a  different  species,  even  though  it  be  nearly  related.  One  of 
the  most  remarkable  examples  of  this  form  of  tolerance  is  met  with  in 
the  hedgehog,  which  resists  large  doses  of  many  very  active  poisons. 
Another  well-known  example  is  the  tolerance  of  the  rabbit  of  large 
quantities  of  atropiue. 

A  form  of  tolerance  which  is  a  matter  of  everyday  observation  is  that 
induced  by  the  prolonged  use  of  a  drug,  which  has  been  called  acquired 
tolerance,  or  mithridatism,  from  the  belief  that  Mithridates  protected 
himself  in  this  way  from  the  danger  of  poisoning.  The  most  familiar 
example  of  this  form  of  tolerance  is  that  acquired  for  tobacco  (nicotine)  ; 
the  first  cigar  often  induces  violent  poisoning,  but  if  a  habit  be  formed, 
considerable  amounts  of  nicotine  may  be  absorbed  without  apparent  harm, 
not  because  the  absorption  is  retarded,  or  the  excretion  is  accelerated, 
but  because  the  tissues  become  accustomed  to  the  presence  of  small 
quantities  of  nicotine,  and  thus  fail  to  react  to  it.  Nicotine,  in  fact, 
becomes  a  normal  constituent  of  the  tissues.  This  tolerance  is  entirely  • 


28  INTRODUCTION. 

different  from  the  immunity  induced  by  toxalbumins  (see  Ricin),  and  it 
is  desirable  that  the  two  terms  should  be  kept  distinct.  Very  often 
while  tolerance  for  a  poison  is  established  in  certain  tissues,  others 
suffer  from  the  prolonged  use  of  excessive  quantities  ;  for  example, 
although  the  seasoned  smoker  does  not  suffer  from  the  nausea  and 
vomiting  which  followed  his  first  essay,  other  organs  may  in  course  of 
time  become  involved,  such  as  the  heart  or  the  eye.  It  is  to  be  noted 
that  tolerance  is  soon  lost  if  the  drug  be  discontinued  for  some  time. 
This  is  of  great  importance  in  cases  of  opium-eating,  for  a  person  who 
has  taken  opium  for  a  long  time  acquires  a  tolerance  for  the  drug,  so 
that  sometimes  enormous  quantities  are  required  in  order  to  induce 
the  ordinary  effects,  but  if  the  habit  be  discontinued  for  some  time 
the  tolerance  is  lost,  and  a  dose  which  would  formerly  have  had  little 
effect  may  now  induce  dangerous  poisoning.  The  prolonged  use  of 
one  drug  may  establish  tolerance  for  others  of  the  same  class.  Thus 
chronic  drunkards  are  not  influenced  by  large  quantities  of  alcohol, 
and  are  also  more  resistant  to  the  action  of  chloroform  than  ordinary 
persons,  this  being  due  to  the  fact  that  chloroform  and  alcohol  act  on 
the  same  nerve  cells  in  the  same  direction,  and  probably  induce  the 
same  changes  in  the  protoplasm. 

The  Cumulative  Effect  of  drugs  is  another  phenomenon  caused  by  their 
prolonged  ingestion.  Small  doses  of  certain  drugs  taken  repeatedly 
for  some  time  eventually  cause  symptoms  which  are  much  more  marked 
than  those  caused  by  a  single  small  dose.  In  many  instances  this 
seems  due  to  the  accumulation  of  considerable  quantities  in  the  tissues. 
The  absorption  may  be  more  rapid  than  the  excretion,  and  each  new 
dose  thus  adds  to  the  total  quantity  in  the  blood  and  organs  more  than 
is  lost  in  the  same  time  by  excretion.  The  classical  example  of  cumu- 
lative action  is  that  of  digitalis,  but  it  is  much  more  frequently  induced 
by  such  drugs  as  mercury,  arsenic,  or  the  iodides,  for  the  so-called 
chronic  poisoning  induced  by  these  is  really  an  example  of  cumulative 
action.  It  has  been  suggested  that  cumulative  action  is  not  really  due 
to  the  accumulation  of  the  drug  in  the  tissues,  but  to  a  summation  of 
a  prolonged  series  of  effects  of  the  same  kind  ;  but  although  the  increase 
of  the  drug  in  the  organs  has  not  been  proved  in  all  instances,  it  seems 
probable  that  this  is  the  explanation  in  the  great  majority  of  cases, 
perhaps  in  all.  Cumulative  action  may  occur  along  with  tolerance,  as 
has  been  stated.  Thus  the  tolerance  of  certain  tissues  for  nicotine  does 
not  protect  others  from  the  effects  of  the  abuse  of  tobacco, 

Synergists.- — The  presence  of  another  drug  having  the  same  effects 
in  the  body  often  increases  the  action  of  a  remedy  to  an  unexpected 
extent.  This  is  the  ground  for  the  prescription  of  several  remedies 
acting  in  the  same  way.1  For  example,  several  purgatives  prescribed 
together  often  act  more  efficiently  than  any  one  given  in  quantity  equal 
to  all  of  them.  It  is  quite  impossible  to  explain  this  except  by 
assuming  that,  although  all  are  alike  in  their  chief  features,  they 
differ  in  the  details  of  their  reactions,  so  that  parts  of  the  alimentary 

1  The  less  important  ones  are  sometimes  termed  adjuvants. 


CONDITIONS  MODIFYING  THE  EFFECTS  OF  DRUGS.  29 

canal  which  might  escape  one  are  affected  by  another,  and  the  mixture 
thus  acts  more  universally  than  any  one  of  the  components.  It  must 
be  added  that,  although  the  greater  efficiency  of  the  mixture  is  attested 
by  the  general  belief  of  physicians,  no  very  satisfactory  researches  on 
the  subject  have  been  carried  out  as  yet. 

On  the  other  hand,  a  drug  may  fail  to  elicit  any  symptoms  if  an 
antagonistic  substance  be  present  in  the  body.  Thus  in  cases  where  a 
powerful  nervous  depressant,  such  as  chloroform,  has  been  inhaled, 
strychnine  may  have  little  or  no  effect  on  the  spinal  cord  in  doses 
which  would  normally  increase  the  reflexes  to  a  marked  extent.  In  the 
same  way,  if  the  terminations  of  the  inhibitory  fibres  of  the  heart  are 
paralyzed  by  atropine,  a  poison  which  normally  slows  the  heart  by 
stimulating  these  terminations  will  have  no  such  effect  except  in  very 
much  larger  doses. 

Similar  modifications  of  the  effects  of  drugs  may  be  induced  by  poi- 
sons induced  by  pathological  changes  in  the  tissues,  or  by  an  unusual 
state  of  irritation  or  of  depression  of  the  tissues  themselves.  For  ex- 
ample, in  hot  weather  and  in  tropical  climates,  purgatives  are  found 
much  more  efficient  than  in  colder  climates,  either  because  there  is 
some  poison  which  acts  along  with  the  purgative,  or  because  the  mucous 
membrane  is  more  irritable  than  usual.  That  some  such  factor  is 
present  in  these  conditions,  is  shown  by  the  frequent  occurrence  of 
diarrhoaa  without  the  use  of  drugs. 

Similarly  when  an  antagonistic  poison  is  formed  in  the  tissues  in  the 
course  of  a  disease,  a  drug  may  have  little  or  no  effect ;  so  that  if  the 
inhibitory  cardiac  terminations  are  paralyzed  by  disease,  the  heart 
cannot  be  slowed  by  muscarine  or  digitalis. 

Pathological  conditions  very  often  modify  the  effects  of  drugs  to  a 
very  considerable  extent,  and  in  a  way  which  cannot  be  explained  at 
present.  For  example,  the  antipyretics  reduce  the  temperature  in 
fever,  but  have  no  effect  on  it  in  health ;  the  bromides  lessen  the  con- 
vulsions in  epilepsy,  but  have  much  less  effect  in  depressing  the  brain 
in  normal  persons.  The  question  may  therefore  be  raised  whether 
the  examination  of  the  effects  of  drugs  in  normal  animals  is  of  much 
value  in  indicating  their  therapeutic  action.  But  in  reply  it  may  be 
said  that  in  a  large  number  of  instances  drugs  are  given,  not  in  order 
to  act  upon  the  diseased  tissues,  but  upon  healthy  ones.  The  object  of 
the  therapeutist  is  very  generally  not  to  restore  the  diseased  tissue, 
but  to  relieve  it  from  work,  and  to  allow  it  rest  so  as  to  promote  its 
restoration  by  nature.  For  instance,  in  disease  of  the  cardiac  valves, 
drugs  are  given  not  with  the  object  of  restoring  their  integrity,  but  to 
act  upon  the  healthy  heart  muscle,  and  to  obviate  the  disturbance 
of  the  circulation  which  is  caused  by  the  destruction  of  the  valves.  In 
inflammation  of  the  kidneys,  the  physician  seldom  attempts  to  reduce 
the  inflammation  by  the  action  of  drugs  on  the  cells  involved,  but 
confines  his  attention  to  removing  by  other  channels  the  products  of 
tissue  waste,  which  would  normally  be  excreted  by  the  kidney.  So 
that  in  most  instances  drugs  are  given  to  act  on  normal  tissues,  or  on 


30  INTRODUCTION. 

tissues  which  are  so  little  affected  by  disease  that  they  react  to  reme- 
dies in  the  same  way  as  the  normal.  In  other  cases  in  which  the 
remedy  acts  on  the  cause  of  the  disease  or  on  the  diseased  tissue,  its 
introduction  is  due  to  clinical  experience  only.  Thus  quinine  destroys 
the  organism  of  malarial  fever,  but  this  could  never  have  been  antici- 
pated from  its  action  on  the  normal  tissues,  and  could  only  be  discov- 
ered by  experiments  on  the  organism,  or  rather  by  experiments  on 
persons  suffering  from  the  disease,  as  the  organism  has  been  recog- 
nized only  of  late  years. 

METHODS  OF  ADMINISTRATION. 

The  effect  of  a  remedy  is  often  determined  very  largely  by  the 
method  in  which  it  is  administered.  As  regards  the  local  action,  this 
is  sufficiently  obvious,  for  an  irritant  applied  to  the  skin  could  scarcely 
be  expected  to  cause  the  same  symptoms  as  if  it  were  applied  to  the 
stomach  and  intestine.  But  the  same  holds  true  for  the  general  action 
in  most  instances,  because  some  tissues  and  organs  absorb  much  more 
rapidly  than  others,  and  a  larger  quantity  of  the  drug  therefore  passes 
through  them  into  the  blood  in  a  given  time.  Thus,  if  a  poison  which 
is  absorbed  slowly  be  rapidly  excreted,  so  little  of  it  may  exist  in  the 
blood  and  tissues  at  any  given  time  that  no  effects  are  induced,  while 
if  it  be  rapidly  absorbed,  the  same  dose  can  exert  some  action  before  it 
is  excreted. 

Drugs  are  applied  for  their  Local  Action  to  the  skin,  to  the  mucous 
membranes  of  the  alimentary,  respiratory,  and  genito-urinary  tracts, 
and  to  the  conjunctiva  and  cornea.  Not  infrequently  they  are  injected 
by  means  of  the  hypodermic  needle  into  the  subcutaneous  tissues  for 
their  local  effects,  and  the  attempt  is  continually  being  renewed  to 
treat  even  the  deeper  tissues  and  organs  locally  by  the  injection  of 
remedies  into  them.  The  objects  of  local  medication  are  very  diverse, 
and  can  be  treated  of  only  in  connection  with  the  individual  drugs. 
The  methods  of  application  are  also  so  numerous  that  only  a  few  of  the 
chief  can  be  mentioned.  Drugs  intended  for  application  to  the  skin 
are  often  formed  into  salves  or  ointments  (unguenta)  by  mixing  them 
with  oily  or  fatty  substances,  which  adhere  to  the  skin  and  do  not 
dry  up,  and  which  in  addition  to  serving  as  a  means  of  applying  an 
active  substance,  protect  the  surface  from  the  air  and  from  irritation. 
Other  preparations  for  application  to  the  skin,  such  as  the  plasters 
(ernplastra),  resemble  the  ointments  in  their  general  characters,  but 
also  give  mechanical  support,  and  bind  surfaces  together  from  their 
being  spread  on  paper  or  cloth,  which  thus  serves  as  a  flexible  splint. 
The  collodions  and  cerates  resemble  the  plasters,  the  oleates  the  oint- 
ments. In  addition  to  these  special  preparations,  drugs  may  be  ap- 
plied to  the  skin  in  solutions,  or  as  powders,  or  solid  masses  may  be 
used  to  cauterize  it. 

The  methods  of  applying  drugs  to  the  alimentary  tract  and  to  the 
lungs  for  their  local  action  are  for  the  most  part  similar  to  those  used 


METHODS  OF  ADMINISTRATION.  31 

for  drugs  which  are  intended  to  be  absorbed.  The  mouth  and  throat 
may  be  washed  out  with  solutions,  which  are  gargled  (gargarismata), 
or  may  be  treated  with  powders,  or  lozenges  (trochisci),  which  are 
slowly  dissolved  and  thus  permit  of  a  more  prolonged  and  constant 
action  in  the  mouth  than  is  possible  if  the  drug  be  swallowed  imme- 
diately. The  nose  may  be  washed  out  with  solutions  of  active  drugs, 
or  powders  may  be  drawn  into  the  nostrils  as  snuffs ;  the  latter  often 
cause  sneezing,  and  are  sometimes  known  as  sternutatories,  or  errhines. 
The  larynx  may  be  treated  locally  by  the  application  of  powders  or 
of  very  small  quantities  of  fluids  by  means  of  the  laryngoscopic  mirror 
and  probe.  Solutions  are  generally  used  for  application  to  the  con- 
junctiva, but  a  more  permanent  effect  can  often  be  obtained  from  the 
use  of  ointments  or  powders  which  are  less  liable  to  be  washed  away 
by  the  tears.  The  urethra,  vagina  and  uterus  are  treated  by  the  in- 
jection of  solutions,  or  by  ointments  and  powders.  Bougies,  which 
are  occasionally  advised,  are  formed  by  incorporating  an  active  drug  in 
some  substance  which  is  solid  at  ordinary  temperatures,  but  melts 
when  introduced  into  the  organ  and  allows  the  drug  to  come  into  con- 
tact with  the  surface.  The  rectum  may  similarly  be  treated  by  the  in- 
jection of  drugs  in  solution  or  suspension  (enemata),  or  by  the  use  of 
suppositories.  Drugs  are  not  infrequently  applied  by  the  rectum  in 
order  to  elicit  their  action  after  absorption,  but  much  oftener  for  their 
local  action  on  the  bowel.  Enemata  may  be  either  large  (a  pint  or 
more)  or  small  (2—5  c.c.,  \— 1  fl.  dr.).  The  large  enemata  are  used 
either  to  wash  out  the  intestines,  and  may  then  contain  an  antiseptic 
or  astringent,  or  to  induce  peristalsis  and  evacuation  of  the  bowel, 
when  they  are  made  up  of  water  with  or  without  soap  or  other  slightly 
irritant  substances.  The  small  enemata  are  used  chiefly  to  induce 
evacuation,  and  contain  more  irritant  substances,  such  as  glycerin 
alone  or  along  with  some  more  active  body  (see  uses  of  the  vegetable 
purgatives).  The  suppositories  are  formed  of  cacao-butter,  which  is 
solid  at  room  temperatures,  but  melts  at  the  temperature  of  the  rectum. 

All  the  visible  mucous  membranes  may  also  be  cauterized  by  the 
application  of  a  solid  rod  of  a  corrosive  for  a  short  time. 

Drugs  whose  General  Action  is  to  be  elicited  after  their  absorption 
are  given  by  the  mouth,  except  when  some  special  character  in  them  or  in 
the  disease  renders  some  other  method  preferable.  They  may  be  given 
by  the  mouth  in  solution  in  water,  alcohol,  oils,  or  other  more  or  less 
indifferent  bodies.  The  disagreeable  taste  of  many  remedies,  however, 
often  precludes  this  method,  and  these  may  be  ordered  in  the  form  of 
pills,  or  in  capsules,  which  are  formed  of  gelatin  or  similar  substances  and 
are  dissolved  in  the  stomach  and  intestines.  Very  often  the  disagree- 
able taste  may  be  concealed  by  the  addition  of  sugar,  or  of  some  strongly 
tasting  but  agreeable  body  such  as  a  volatile  oil.  Insoluble  drugs  may 
be  given  as  powders,  as  they  have  little  or  no  taste.  Powders  are  also 
used  as  a  means  of  administering  soluble  drugs,  if  they  have  not  a  dis- 
agreeable taste  and  have  no  marked  local  action,  but  very  deliquescent 
drugs  should  not  be  given  in  this  form.  Insoluble  drugs  are  sometimes 


32  INTRODUCTION. 

ordered  in  suspension  in  mucilaginous  fluids ;  and  oils,  which  are  dis- 
tasteful to  many  people,  may  be  given  mixed  with  water  and  gums 
(emulsions). 

The  rate  of  absorption  from  the  alimentary  canal  varies  greatly 
with  different  drugs  and  also  with  the  form,  in  which  they  are  adminis- 
tered. The  first  point  will  be  treated  of  in  connection  with  the  indi- 
vidual drugs.  As  regards  the  second,  it  may  be  stated  that  drugs  are 
more  rapidly  absorbed  when  they  are  swallowed  in  solution,  and  that 
when  much  inert  and  insoluble  matter  is  associated  with  them,  their 
absorption  is  much  retarded.  Thus,  common  salt  passes  more  rapidly 
into  the  blood  when  it  is  dissolved  before  being  taken  than  when  it  is 
swallowed  dry,  and  morphine  is  absorbed  much  more  quickly  when  it  is 
administered  pure  than  when,  as  in  opium,  it  is  mixed  with  a  mass  of 
gums  and  other  bodies.  This  fact  is  taken  advantage  of  in  practice  by 
giving  drugs  in  solution  when  rapid  absorption  is  desirable,  and  by  giv- 
ing less  pure  forms  when  the  local  action  on  the  stomach  and  bowel 
is  .to  be  elicited.  The  more  concentrated  the  solution,  the  greater  is 
the  irritant  action  on  the  stomach,  and  thu?  where  irritation  of  the 
stomach  is  desired,  either  the  solid  drug  or  a  strong  solution  is  given  ; 
but  as  a  general  rule  the  local  action  on  the  stomach  is  to  be  avoided,  and 
drugs  are  therefore  ordered  in  as  dilute  solution  as  is  possible  without 
increasing  the  bulk  to  too  great  an  extent.  It  is  to  be  noted  that 
drugs  which  are  insoluble  in  the  test-tube  may  be  rendered  soluble  by 
the  action  of  the  gastric  and  intestinal  juices,  while  many  which  are 
given  in  solution,  are  thrown  down  in  the  stomach  in  the  form  of 
insoluble  albuminates. 

The  great  mass  of  drugs  absorbed  from  the  stomach  and  intestine 
is  carried  to  the  liver  before  reaching  the  general  circulation,  and  this 
is  of  great  importance  in  determining  their  effects  in  the  body,  as  some 
of  them  are  retained  in  that  organ,  and  are  either  entirely  destroyed  or 
escape  so  slowly  that  they  have  no  perceptible  effect. 

Another  important  method  of  administering  drugs  for  their  general 
action  and  also  for  their  local  effects  is  by  inhalation  into  the  lungs. 
Only  volatile  drugs  can  be  used  thus  for  their  general  action.  They 
are  absorbed  very  rapidly  owing  to  the  extensive  surface  to  which  they 
are  applied,  and  also  because  volatile  substances  penetrate  the  tissues 
more  readily  than  others.  The  best  examples  of  inhalation  are  offered 
by  the  general  anaesthetics,  chloroform  and  ether.  Most  substances 
absorbed  by  the  lungs  are  also  excreted  by  them,  and  this  leads  to  an 
important  practical  point  in  regard  to  the  anaesthetics.  For  the  passage 
of  gases  or  vapors  through  the  lining  epithelium  of  the  alveoli  depends 
in  most  instances  *  upon  their  partial  pressure,  that  is,  upon  their  con- 
centration in  the  air  and  blood  respectively.  Accordingly,  when  the  air 
contains  more  chloroform  vapor  than  the  blood,  the  anaesthetic  passes 
into  the  blood,  but  as  soon  as  the  condition  is  reversed,  and  the  blood 
contains  more  chloroform  than  the  air  of  the  alveoli,  it  commences  to 

1  Such  gases  as  oxygen  and  carbon  monoxide,  which  form  chemical  combinations 
with  the  haemoglobin,  are  of  course  exceptions. 


METHODS  OF  ADMINISTRATION.  33 

pass  backwards.  The  more  concentrated  the  vapor  inhaled,  the  more 
chloroform  is  contained  in  the  cubic  centimeter  of  blood,  and  the  greater 
is  the  action  on  the  nervous  centres  and  the  heart. 

Less  volatile  substances  are  sometimes  inhaled  into  the  lungs  for 
their  local  action,  and  even  non-volatile  bodies  suspended  in  a  spray 
of  vapor  may  be  thrown  into  the  respiratory  passages,  but  it  may  be 
questioned  whether  these  last  really  reach  the  alveoli  except  in  traces. 

Drugs  are  also  applied  to  the  skin  in  order  to  elicit  their  general 
action.  Volatile  bodies  are  certainly  absorbed  by  it,  although  much 
more  slowly  than  by  the  lungs  or  by  the  stomach  and  intestine.  Solu- 
tions in  water  of  non-volatile  drugs  are  not  absorbed  from  the  skin,  but 
solutions  of  certain  remedies  in  alcohol,  oils,  fats,  ether,  and  some  other 
substances  which  are  capable  of  dissolving  or  mixing  with  the  fatty 
covering  of  the  skin,  are  absorbed  fairly  rapidly  if  they  are  rubbed  in 
thoroughly.  This  method  of  application  (inunction)  has  been  used 
chiefly  for  the  absorption  of  mercury,  as  the  local  action  on  the  stomach 
and  bowel  is  thus  avoided.  (See  Mercury.)  Alkaloids  do  not  appear 
to  be  absorbed  by  the  skin  even  when  dissolved  in  oils  or  alcohol.  An 
entirely  obsolete  method  of  application  is  the  endermic,  in  which  the 
epidermis  was  removed  by  a  blister,  and  the  remedy  then  applied  to 
the  exposed  corium. 

The  hypodermic  method  is  of  comparatively  recent  origin,  but  is 
being  more  widely  used  every  year.  In  it  drugs  are  injected  through 
a  fine  hollow  needle  into  the  subcutaneous,  or,  in  the  case  of  more 
irritant  substances,  into  the  muscular  tissue,  where  they  meet  with 
fewer  sensory  nerves.  Absorption  occurs  more  rapidly  than  when 
drugs  are  given  by  the  mouth,  the  local  action  on  the  alimentary 
canal  is  avoided,  and  the  physician  is  more  certain  that  the  whole 
of  the  remedy  is  effective,  provided  it  is  soluble  and  is  not  pre- 
cipitated at  the  point  of  injection.  At  the  same  time,  the  method 
has  certain  drawbacks,  the  chief  of  which  are  the  pain  of  the  injec- 
tion and  the  danger  of  injecting  a  powerful  remedy  into  one  of  the 
subcutaneous  veins.  Hypodermic  injections  should  be  made  only 
by  the  physician  or  trained  attendant,  for  incalculable  injury  has 
been  done  by  entrusting  patients  with  the  syringe,  particularly  for  the 
injection  of  morphine  and  cocaine.  The  needle  and  syringe  ought  to 
be  disinfected,  and  the  substance  injected  should  be  aseptic,  and  this 
renders  the  method  inconvenient.  As  a  general  rule,  solutions  in 
water  or  in  dilute  alcohol  are  used  for  injection,  but  the  insoluble 
salts  of  mercury  have  also  been  injected,  suspended  in  oil  (see  Mer- 
cury). Irritant  drugs  are  to  be  avoided  as  far  as  possible,  as  they 
cause  great  pain,  swelling  and  sometimes  suppuration,  even  when  the 
injection  has  been  carried  out  aseptically.  Hypodermic  injection  is  used 
very  largely  to  elicit  the  general  action  of  a  remedy,  but  also  for 
the  local  effects,  as  when  cocaine  is  injected  in  order  to  produce  local 
anaesthesia.  Solutions  of  inert  bodies  have  also  some  anaesthetic  action, 
probably  owing  to  their  mechanical  action  on  the  sensory  nerve  fibres. 
As  the  absorption  from  the  subcutaneous  tissues  is  so  much  more  rapid 
3 


34  INTRODUCTION. 

than  that  from  the  stomach  and  intestine,  when  the  drug  is  in  perfect 
solution  the  dose  has  to  be  reduced.  As  a  general  rule,  about  one- 
half  of  the  ordinary  amount  is  sufficient. 

Deeper  injections  are  sometimes  made  for  their  local  action  on  the 
organs.  Thus,  antiseptics  have  been  injected  into  lung  cavities,  caustics 
have  been  injected  into  tumors,  and  direct  applications  have  been  made 
to  the  nerves  in  sciatica  and  other  similar  disorders. 

Intravenous  injection  is  the  most  certain  method  of  bringing  drugs 
into  the  circulation  and  tissues,  and  is  at  the  same  time  the  most  rapid. 
It  is,  therefore,  very  largely  used  in  experiments  on  animals,  but 
has  generally  been  considered  too  dangerous  for  therapeutic  purposes 
in  man.  Baccelli  has,  however,  recommended  it  highly  in  recent  years 
in  cases  of  emergency,  in  which  the  immediate  action  of  a  remedy  is 
required.  In  pernicious  malaria,  and  in  syphilis  when  an  important 
organ  is  threatened,  he  has  injected  small  quantities  of  quinine  and 
mercury  with  great  success.  The  dose  must  be  very  much  smaller 
than  that  employed  by  the  mouth,  but  it  is  impossible  as  yet  to  state 
exactly  what  fraction  will  induce  the  same  effects. 

Drugs  are  occasionally  applied  by  the  rectum  for  their  general  action, 
as  has  been  mentioned.  The  local  effects  on  the  stomach  are  avoided 
by  this  method,  and  morphine  and  opium  are,  therefore,  not  infrequently 
administered  thus.  The  rate  of  absorption  from  the  rectum  as  com- 
pared with  that  from  the  stomach  and  bowel  is  still  a  disputed  point, 
and  some  physicians  recommend  that  the  dose  be  reduced  to  three- 
fourths,  while  others  recommend  one  and  one-half  times  that  given  by 
the  mouth. 

Drugs  are  not  administered  by  the  other  mucous  membranes  for  their 
general  effects,  but  it  must  not  be  forgotten  that  symptoms  may  arise 
from  their  application  to  them  for  their  local  action.  Similarly,  drugs 
applied  as  dressings  to  wounds  or  abrasions  have  very  often  given  rise  to 
severe  or  fatal  poisoning  from  being  absorbed  into  the  blood  and  tissues. 

THE  CHEMICAL  CHARACTERS  OF  DRUGS. 

An  enormous  number  of  substances  induce  changes  in  the  living 
organism,  and  have,  therefore,  to  be  recognized  in  pharmacological 
treatises.  Many  of  them  are  comparatively  simple  chemical  com- 
pounds, and  require  no  general  description  here,  but  less  attention  is 
paid  in  ordinary  chemical  text-books  to  certain  groups  of  active  poisons, 
and  some  note  must  be  taken  of  their  general  properties. 

In  the  inorganic  materia  medica  are  found  many  salts,  bases,  and 
acids,  and  a  few  uncombined  elements,  such  as  mercury  and  phosphorus. 

Organic  chemistry  offers  a  large  and  ever-increasing  number  of  arti- 
ficial compounds  which  belong  to  almost  every  one  of  the  divisions 
recognized  in  chemistry.  The  hydrocarbons,  alcohols,  ethers,  phenols, 
ketones,  aldehydes,  acids,  and  many  others,  contribute  active  agents, 
and  in  fact  most  of  them  are  represented  by  one  or  more  members  in 
therapeutics.  They  may  all  be  regarded  as  sufficiently  known  by  stu- 


THE  CHEMICAL  CHARACTERS  OF  DRUGS.  35 

dents  who  are  prepared  to  study  pharmacology  with  profit,  but  some 
substances,  obtained  chiefly  from  plants,  require  further  mention. 

The  first  group  of  these  is  formed  by  the  Alkaloids,  which  are 
substituted  ammonias,  and  have  a  more  or  less  strongly  alkaline  re- 
action, so  that  they  are  often  known  as  the  vegetable  bases.  They 
contain  carbon,  hydrogen,  nitrogen,  and,  as  a"  general  rule,  oxygen, 
although  some  of  them,  such  as  coniine,  are  devoid  of  it.  Like  am- 
monia, they  combine  with  acids  readily  without  eliminating  hydrogen, 
arid  the  salts  thus  formed  resemble  those  of  ammonia  in  many  respects, 
among  others  in  being  thrown  out  of  combination  by  the  fixed  alkalies. 
The  term  alkaloid  is  often  restricted  to  compounds  of  pyridine  and 
quinoline,  but  this  narrow  definition  cannot  be  maintained  in  treating 
them  from  the  pharmacological  point  of  view.  It  is  true  that  most 
of  the  vegetable  alkaloids  whose  constitution  is  known  are  derived  from 
pyridine,  quinoline  and  isoquinoline  by  the  addition  of  hydrogen,  and 
generally  by  the  substitution  of  one  or  more  of  the  hydrogen  atoms  by 
side  chains  of  greater  or  less  complexity. 

CH  CH 


HC/       \CH 


Hd\>H 

N  c: 


Pyridine.  Quinoline. 

But  others  appear  to  be  derivatives  of  the  pyrrol  and  oxazine  groups, 
while  in  others  the  nitrogen  is  attached  to  radicles  belonging  to  the 
methane  or  open-chain  series,  as  in  CH(OH)2  —  CH2  —  N(CH3)3OH, 
which  is  generally  regarded  as  the  formula  of  muscarine.  Another 
series  of  bodies,  which  may  be  regarded  as  alkaloids,  although  they 
differ  from  the  others  in  many  respects,  are  derivatives  of  aniline,  and 
are  artificial  products. 

CH  o 


HC 


HC 


/\  y\ 

C-NH2  HC  /      \CH 

CH  HCk  JCH  Hcl  ICH 


N 

Pyrrol.  Aniline.  Oxazine. 

These  aniline  derivatives  bear  some  relation  to  the  vegetable  bases 
in  their  action,  but  are  equally  or  more  nearly  related  to  the  benzol 
series,  so  that  they  may  be  regarded  as  connecting  links  between  these 
two  classes  of  bodies.  Finally  the  purine  bodies  (see  Caffeine  group) 
may  be  mentioned  in  this  connection,  although  their  chemical  structure 
scarcely  permits  of  their  being  numbered  among  the  true  alkaloids. 

Some  of  the  vegetable  alkaloids  have  been  formed  synthetically  in 
the  laboratory,  and  the  constitution  of  some  of  the  others  is  perfectly 
well  known,  but  many  of  them  have  not  yet  been  isolated,  and  there 
are  probably  others  whose  existence  is  not  even  suspected.  These  vege- 
table alkaloids  occur  in  almost  all  parts  of  plants,  although  they  are 


36  INTR  OD  UCTION. 

found  in  greatest  abundance  in  the  seeds  and  roots.  The  same  alka- 
loid is  often  found  in  most  of  the  plants  of  a  genus,  or  it  may  occur  in 
one  or  two  species  of  a  genus  and  in  other  plants  which  are  in  no  way 
related.  Very  often  more  than  one  alkaloid  is  found  in  a  plant,  and 
these  may  differ  entirely  in  their  action  on  animals,  although  not  in- 
frequently all  the  alkaloids  of  a  plant  resemble  each  other  in  their 
effects.  The  alkaloids  are  found  almost  exclusively  in  dicotyledonous 
plants,  only  one  or  two  being  known  to  exist  in  the  monocotyledons. 
Muscarine  is  found  in  the  fungi,  and  quite  recently  alkaloids  have 
been  isolated  from  the  suprarenal  capsule  of  animals  and  from  the  skin 
of  the  salamander. 

The  alkaloids  are  very  often  only  slightly  soluble  in  water,  but 
form  salts  which  are  generally  more  soluble.  Many  of  the  bases  are 
dissolved  in  ether,  chloroform  and  amyl  alcohol,  while  the  salts  are  in- 
soluble in  these.  Both  bases  and  salts  are  generally  fairly  soluble  in 
alcohol.  The  alkaloids  are  precipitated  from  solution  by  a  large  num- 
ber of  reagents,  of  which  the  most  important  are  the  chlorides  of 
platinum  and  of  gold,  tannic  acid,  phosphotungstic  and  phosphomo- 
lybdic  acid,  the  double  iodides  of  potassium  and  mercury,  and  of  po- 
tassium and  cadmium,  and  iodine  held  in  solution  in  water  by  potassic 
iodide.  The  hydrates  and  carbonates  of  the  alkalies  and  the  alkaline 
earths  precipitate  the  alkaloids  from  solutions  of  the  salts  in  water,  a 
point  of  some  importance  in  prescribing  these  bodies.  In  cases  of 
poisoning  when  the  alkaloid  has  been  taken  by  the  mouth,  it  may  be 
precipitated  in  the  stomach  by  dilute  alkalies  or  better  by  tannin  solu- 
tions. The  poison  should  then  be  removed  by  inducing  vomiting  or 
by  washing  out  the  stomach  with  the  stomach  tube. 

Another  important  class  of  vegetable  poisons  is  formed  by  the  Glu- 
cosides  (glycosides),  or  saccharides,  which  are  esters  (compound  ethers) 
composed  of  sugars  and  hydroxyl  substances,  and  which  liberate 
sugar  when  they  are  heated  with  acids,  or  sometimes  with  alkalies,  or 
when  certain  unorganized  ferments  act  on  them.  The  sugar  formed  in 
this  way  is  often  glucose,  but  not  invariably  so ;  the  other  decompo- 
sition products  have  been  identified  only  in  a  few  instances.  Many  of 
the  glucosides  contain  only  carbon,  hydrogen  and  oxygen,  a  few  have 
nitrogen  in  addition  and  one  or  two  sulphur.  In  some  instances  the 
remainder,  after  the  sugar  is  split  off,  is  an  alkaloid,  e.  g.,  solanidine. 
Glucosides  differ  greatly  in  their  solubility  in  water  and  alcohol ;  com- 
paratively few  of  them  are  soluble  in  ether.  Some  of  the  glucosides 
are  powerful  poisons,  others  have  little  or  no  action. 

Resins,  an  ill-defined  group,  are  found  in  many  plants,  and  are 
characterized  by  their  smooth,  shining  fracture,  and  by  their  insolubility 
in  water  and  solubility  in  ether,  chloroform,  volatile  oils,  benzol  and,  in 
many  cases,  in  alcohol.  They  seem  to  be  formed  in  plants  by  the  oxi- 
dation of  volatile  oils,  and  are  often  acid  or  anhydride  in  character, 
while  others  are  apparently  alcohols  or  esters.  The  resins  are  almost 
invariably  composed  of  several  different  substances  mixed  together. 
Many  of  the  resins  are  local  irritants,  and  some  are  poisonous  in  com- 


PHARMACOPEIAS  AND  PHARMACOPCEIAL  PREPARATIONS.      37 

paratively  small  quantity  from  the  powerful  action  they  exert  on  the 
intestine. 

Oleoresins  are  solutions  of  resins  in  ethereal  oils,  which  lend  them  a 
characteristic  odor  and  taste. 

The  term  '  Balsam '  is  often  used  as  synonymous  with  oleoresin, 
but  most  writers  restrict  it  to  those  oleoresins  which  contain  ben- 
zoic  and  cinnamic  acid  along  with  other  constituents.  (See  Benzoic 
Acid.) 

Gumresins  are  mixtures  of  resins  and  gums,  generally  containing  some 
volatile  oils.  They  are  insoluble  in  water,  but  the  resin  is  suspended 
in  it  by  the  gum.  On  the  other  hand,  the  resin  is  dissolved  by  alcohol, 
while  the  gum  remains  insoluble. 

Gums  are  amorphous,  transparent  substances,  composed  of  carbohy- 
drates of  the  formula  C6H10O5  and  are  thus  nearly  related  to  cellu- 
lose and  starch.  Some  of  them  are  soluble  in  water,  while  others 
merely  swell  to  a  jelly  in  it ;  they  are  insoluble  in  alcohol.  They 
generally  occur  in  plants  in  combination  with  calcium,  magnesium  or 
potassium  ;  they  have  no  poisonous  action,  but  form  a  protective  cover- 
ing for  irritated  surfaces,  and  are  largely  used  to  suspend  in  water  sub- 
stances which  are  insoluble  in  it,  such  as  resins  and  oils. 

Volatile  oils  occur  in  plants  in  large  numbers.     (See  page  61.) 

Many  Acids  which  are  of  pharmacological  and  therapeutic  interest 
are  obtained  from  plants,  but  it  is  unnecessary  to  enter  into  a  descrip- 
tion of  their  properties  here. 

Fats  and  oils,  sugars,  starch,  proteids,  coloring  matter,  ferments  and 
other  bodies  which  occur  in  plants,  and  are  contained  in  many  of  the 
preparations  used  in  therapeutics,  are  not  generally  possessed  of  any 
action  of  importance.  Those  which  are  active  in  the  body  will  be 
described  individually. 

Finally  many  of  the  active  principles  of  plants  are  entirely  unknown 
or  have  been  only  partially  examined.  Among  these  are  a  number  of 
substances  which  have  little  in  common  except  their  bitter  taste  and 
which  are  known  as  Bitters. 


THE  PHARMACOPEIAS  AND  PHARMACOPCEIAL 
PREPARATIONS. 

Almost  all  governments  have  found  it  necessary  to  regulate  the 
preparation  of  drugs  used  in  therapeutics,  and  for  this  purpose  issue  at 
intervals  codes  of  instructions  defining  the  characters  of  the  drugs  and 
giving  the  exact  formulae  according  to  which  they  are  to  be  prepared 
for  use.  In  the  United  States,  where  the  government  has  not  un- 
dertaken this  as  yet,  a  code  has  been  prepared  by  a  voluntary  asso- 
ciation of  physicians  and  pharmacists.  These  codes  are  known  as 
Pharmacopoeias,  and  some  differences  exist  between  those  of  different 
states,  although  the  most  important  drugs  are  found  in  all  of  them. 
All  the  drugs  used  in  therapeutics  are  not  found  in  the  pharmacopoeias, 
for  these  are  issued  only  at  intervals  of  several  years,  and  in  the  mean- 


38  INTRODUCTION. 

time  large  numbers  of  remedies  are  introduced,  used  for  a  few  months, 
and  pass  into  oblivion.  Even  when  a  drug  maintains  its  position  for 
many  years,  and  promises  to  be  a  lasting  addition  to  therapeutics,  it 
often  fails  to  be  admitted  to  the  official  code,  while  others  of  older 
standing,  which  are  comparatively  seldom  used,  and  which  might  be 
omitted  without  loss,  are  kept  on  the  list.  This  conservative  tendency 
of  the  compilers  of  the  pharmacopeias  has  its  disadvantages,  but  at  any 
rate  tends  to  withhold  official  sanction  from  the  innumerable  ephemeral 
products  of  chemical  industry.  The  official  definition  of  therapeutic 
substances  is  of  advantage  to  both  physician  and  pharmacist,  as  it 
assures  the  former  that  the  drug  he  prescribes  will  have  a  uniform 
quality,  wherever  in  the  country  it  is  dispensed,  while  the  pharmacist 
is  saved  from  the  continual  preparation  of  remedies  in  different  forms, 
by  their  being  prescribed  in  one  recognized  strength. 

The  pharmacopeias  contain  a  large  number  of  pure  substances  such 
as  salts,  acids,  bases,  alkaloids,  and  these  require  no  further  description. 
On  the  other  hand,  many  of  the  drugs  are  given  in  an  impure  form, 
either  because  the  active  principle  is  unknown,  or  because  its  isolation 
is  attended  with  difficulty  and  expense.  Thus  many  of  the  vegetable 
remedies  are  presented  in  the  pharmacopoeias  as  solutions  or  solids  which 
contain  not  only  the  active  principle  but  gums,  sugars,  coloring  matter, 
and  many  other  impurities.  These  are  provided  in  different  forms  to 
allow  of  variation  in  their  administration.  In  addition,  the  pharma- 
copoeias contain  a  number  of  official  prescriptions,  that  is,  mixtures 
of  active  substances  in  such  proportions  as  are  ordinarily  prescribed. 
These  are  generally  designated  by  the  addition  of  compound  (compo- 
situs)  to  the  name  of  the  chief  ingredient.  Most  pharmacopoeias 
continue  to  use  Latin  in  the  titles  of  the  drugs,  and  this  is  not  due  to 
mere  pedantry  or  conservatism,  as  is  often  stated.  For  the  popular 
name  of  a  drug  is  often  used  for  several  different  substances,  as,  for 
example,  hellebore,  while  the  Latin  name  in  a  prescription  indicates 
that  drug  which  is  known  by  the  term  in  the  pharmacopoeia.  In  the 
same  way  it  is  found  necessary  to  maintain  Latin  terms  in  botany  and 
zoology  in  order  to  define  accurately  the  species. 

Many  crude  or  unprepared  drugs  are  found  in  the  pharmacopoeias, 
such  as  leaves,  roots,  flowers,  or  even  whole  plants.  These  are  used 
chiefly  for  the  preparation  of  other  more  readily  applicable  remedies, 
but  are  sometimes  prescribed  as  powders  or  in  pills. 

The  following  preparations  l  are  official  : 

a.  Aqueous  Preparations. 

Aquse,  medicated  waters,  generally  contain  only  traces  of  some  volatile 
substance,  such  as  an  ethereal  oil  or  chloroform,  in  solution  in  water,  and 
these  are  used  in  prescriptions  as  more  agreeable  to  the  taste  and  smell  than 
pure  water  but  have  no  farther  effect.  In  the  U.  S.  P.  the  solutions  of 

1  The  student  is  advised  to  omit  the  following  list  for  the  present,  and  to  refer  to  it 
only  as  he  takes  up  the  preparations  of  the  individual  drugs.  Most  of  these  prepara- 
tions are  found  in  both  pharmacopoeias.  Those  which  occur  only  in  the  British  are  indi- 
cated by  B.  P.,  while  those  which  are  confined  to  the  United  States  are  marked  U.  S.  P. 


PHARMACOPCEIAS  AND  PHARMACOPCEIAL  PREPARATIONS.      39 

chlorine,  ammonia  and  hydrogen  peroxide  are  also  included  under  aquse,  but 
these  are  used  only  to  elicit  the  specific  effects  of  these  drugs  and  are  power- 
ful poisons.  In  the  B.  P.  these  strong  solutions  are  included  in  the  liquores. 

Liquores  (U.  S.  P.)  are  solutions  in  water  of  soluble  substances  which  are 
not  volatile.  The  official  solutions  of  powerful  poisons  are  often  one  per 
cent,  in  strength. 

Liquores  (B.  P.)  are  solutions  in  the  widest  sense,  in  water,  alcohol,  or 
other  fluids.  The  dissolved  substance  may  be  volatile  or  non-volatile.  The 
"concentrated  solutions"  (B.  P.,  Liquores  Concentrati)  are  not,  as  might  be 
supposed,  condensed  by  evaporation.  They  resemble  infusions  and  decoc- 
tions in  most  respects. 

Decocta,  or  decoctions,  are  impure  solutions  of  vegetable  principles,  which 
are  obtained  by  boiling  parts  of  plants  in  water. 

Jn/wsa,  or  infusions,  are  solutions  obtained  by  soaking  parts  of  plants  in 
water,  which  may  be  hot  or  cold,  but  is  not  kept  boiling.  Infusions  and 
decoctions  are  weak  preparations  and  decompose  rapidly  so  that  they  are 
used  only  when  recently  prepared. 

Misturse  (U.  S.  P.),  or  mixtures,  are  preparations  in  which  substances  in- 
soluble iu  water  are  suspended  in  it  by  means  of  gums  or  similar  viscid  sub- 
stances. 

Misturse  (B.  P.)  include  a  number  of  preparations  in  which  insoluble  bodies 
are  suspended  in  water  by  means  of  gums  or  syrup,  but  one  mixture  contains 
only  soluble  bodies. 

Emulsa  (U.  S.  P.),  emulsions,  are  formed  by  suspending  oils  in  water  by 
means  of  gums  or  other  viscid  bodies.  The  B.  P.  contains  no  official  emul- 
sions, the  corresponding  preparations  being  known  as  misturse. 

Mucilagines,  mucilages,  are  solutions  in  water  of  gums,  starch,  and  sim- 
ilar bodies. 

Syrupi,  syrups,  are  strong  solutions  of  sugar  in  water,  which  may  be  used 
alone,  or  may  be  impregnated  with  more  active  bodies.  Similar  preparations 
formed  with  honey  instead  of  syrup  (sometimes  known  as  mellita)  are  official, 
as  Mel  Rosse  (U.  S.  P.),  Mel  Boracis  (B.  P.).  A  solution  of  honey  and  acetic 
acid  is  known  as  oxymel  in  the  B.  P.  (Oxymel  Scillse). 

Lotiones  (B.  P.),  lotions,  or  washes.  This  term  is  used  to  designate  two 
preparations  of  mercury,  the  black  and  yellow  wash. 

b.    Alcoholic  Preparations. 

It  is  to  be  noted  that  in  these  preparations  the  menstruum  (alcohol)  is  not 
an  indifferent  body  as  in  the  aqueous  preparations  ;  the  effects  of  some  of 
this  class  are  undoubtedly  due  rather  to  the  alcohol  than  to  the  dissolved 
substances. 

Spirit  us,  spirits,  are  solutions  of  volatile  bodies  in  alcohol,  and  often  owe 
their  chief  action  to  the  solvent  and  not  to  the  drug  contained  in  it. 

Elixiria  (U.  S.  P.),  elixirs,  differ  from  spirits  chiefly  in  containing  sugars, 
which  are  added  in  order  to  give  them  taste. 

Tincturse,  tinctures,  are  solutions  in  alcohol  of  medicinal  substances,  which 
are  generally  formed  by  soaking  parts  of  plants  in  it.  They  contain  both  volatile 
and  non-volatile  ingredients,  but  the  latter  are  generally  the  more  important. 

Fluidextracta  (U.  S.  P.),  Extracta  Liquida  (B.  P.),  fluid  extracts,  are 
prepared  from  plants  by  forming  solutions  in  water  or  more  frequently  in 
alcohol,  and  evaporating  them  until  the  solutions  contain  as  many  cubic 
centimeters  as  the  original  crude  drugs  weighed  in  grammes ;  that  is  the 
volume  of  the  fluid  extract  corresponds  to  the  weight  of  the  crude  drug. 

The  tinctures  and  fluid  extracts  are  the  most  commonly  used  liquid 
preparations,  and  most  of  the  important  drugs  are  prepared  in  one  or  both 
of  these  forms. 

Vina,  medicated  wines,  are  solutions  of  active  substances  in  wine  or  in 
dilute  alcohol. 


40  INTR  01)  UCTION. 

Sued  (B.  P.),  the  juices  of  fresh  green  plants,  obtained  by  pressure.  Some 
alcohol  is  added  to  preserve  them  from  putrefaction. 

c.  Other  Fluid  Preparations. 

Glycerita  (U.  S.  P.)  or  Glycerina  (B.  P.)  are  solutions  of  medicinal  sub- 
stances in  glycerin. 

Collodia,  collodions,  are  solutions  of  medicinal  substances  in  collodion. 
(See  Part  VI.) 

Aceta,  or  medicated  vinegars,  are  solutions  of  medicinal  substances  in 
vinegar  or  acetic  acid. 

Linimenta,  liniments,  embrocations,  are  preparations  in  which  active  rem- 
edies are  dissolved  or  suspended  in  dilute  alcohol,  oils,  or  water.  They  gen- 
erally contain  an  oil  or  soap  and  are  intended  to  be  applied  to  the  skin. 

d.  Solid  and  Semi- Solid  Preparations. 

Extracta,  extracts,  are  formed  from  solutions  such  as  tinctures,  decoctions, 
or  infusions  by  evaporation,  which  is  continued  until  there  remains  a  solid 
mass.  The  extracts  thus  contain  all  the  substances  which  are  taken  up  by 
the  solvent,  except  those  which  are  driven  off  or  decomposed  by  the  temper- 
ature at  which  evaporation  is  carried  on. 

Pilulse,  pills,  are  globular  masses  of  small  size,  such  as  admits  of  their 
being  easily  swallowed.     They  are  formed  from  extracts,  or  from  powders, 
by  the  addition  of  some  substance  to  give  them  the  necessary  cohesion  and 
consistency.     Pills  generally  weigh  0.1-0.3  G.  (2-5  grs.).     The  U.  S.  P.  de- 
termines the  composition  and  size  of  the  official  pills,  so  that  the  dose  can 
be  modified  only  by  ordering  several  pills  to  be  taken  at  one  time.     The  B.  P. 
leaves  the  pills  unformed,  so  that  they  may  be  prescribed  of  any  size.     T1 
Pilulse  of  the  B.  P.  really  correspond  not  to  the  Pilulse,  but  to  the  Massse  * 
the  U.  S.  P. 

Massse  (U.  S.  P.),  masses,  are  preparations  made  up  of  the  proper  consist- 
ency for  pills.  They  are  invariably  prescribed  in  the  form  of  pills. 

Confectiones,  confections  or  electuaries,  are  soft,  solid  preparations  consist- 
ing of  sugar  or  honey  impregnated  with  some  more  active  body. 

Suppositoria,  or  suppositories,  are  intended  for  insertion  into  the  rectum, 
urethra,  or  vagina,  and  are,  except  in  one  or  two  cases,  formed  by  mixing 
the  active  ingredient  with  cacao-butter.  (See  Part  VI. )  Suppositories  for 
the  rectum  are  conical  in  shape  and  weigh  about  a  gramme  (15  grs.).  Those 
for  the  urethra  are  of  the  same  weight,  but  are  pencil- shaped,  while  the 
vaginal  suppositories  are  globular,  and  weigh  about  3  grammes  (45  grs.). 

Pulveres,  powders,  are  simply  dry  substances  in  a  state  of  fine  division. 
Most  of  the  official  powders  are  mixtures  of  several  active  bodies. 

Triturationes  (U.  S.  P.),  trituratibns,  are  formed  from  powders  by  diluting 
them  with  nine  parts  of  sugar  of  milk. 

Trochisci,  troches,  or  lozenges,  are  solid  masses,  generally  of  a  flattened 
shape,  and  consist  of  powders  or  other  bodies,  incorporated  in  sugar  and  gum. 
A  very  friable  form  of  lozenge  known  as  Tabellse,  or  tablet  triturates  (not 
official),  is  formed  by  pressing  in  moulds  a  mixture  of  powdered  sugar  and 
drugs,  slightly  moistened  with  alcohol. 

Lamellse,  (B.  P.),  or  discs,  are  small  discs  formed  of  gelatin  with  some  gly- 
cerin, each  weighing  ^"sV  gr-  They  are  impregnated  with  an  active  drug, 
and  are  applied  to  the  conjunctiva  in  order  to  elicit  the  local  effects. 

Unguenta,  ointments,  salves,  are  soft,  oily  substances  which  are  applied  to 
the  skin  by  rubbing.  (See  page  49.) 

Oleata,  solutions  in  oleic  acid  resembling  the  ointments  in  appearance  and 
uses. 

Cerata  (U.  S.  P.),  cerates,  resemble  ointments,  but  are  rendered  harder  by 
the  addition  of  wax.  (See  page  51.) 


CLASSIFICATION  OF  DRUGS.  41 

Emplastra,  plasters,  are  adhesive  bodies  of  a  still  harder  consistency  than 
cerates,  and  soften  only  when  heated.  (See  Part  VI.) 

ChartsK,  papers,  are  preparations  of  active  substances  which  are  spread  in  a 
thin  layer  upon  paper,  or  are  incorporated  in  it  by  dipping  sheets  of  paper 
into  a  solution. 

UNOFFICIAL  PREPARATIONS. 

Cachets,  are  thin  discs  of  dough  of  the  shape  of  a  soup-plate  and  varying 
from  £  in.  to  1£  in.  in  diameter.  When  two  of  them  are  placed  together 
with  their  concave  sides  toward  each  other,  they  form  a  receptacle  in  which 
powders  are  dispensed.  The  edges  stick  together  when  they  are  moistened. 
A  somewhat  similar  method  of  dispensing  is  in  gelatin  capsules,  which  may 
be  hard  or  soft,  and  which  are  made  in  different  sizes.  The  hard  capsule  is 
used  for  solids,  the  soft  for  liquids.  Sometimes  the  latter  contain  as  much 
as  15  c.c.  (£  fl.  oz.),  but  these  are  difficult  to  swallow. 

Cataplasmata,  or  poultices,  are  not  official  preparations  now,  but  are  in 
common  use.  They  are  generally  made  of  linseed  meal,  oatmeal,  or  bread 
crumb,  which  is  formed  into  a  paste  with  hot  water,  enclosed  in  thin  cotton 
or  linen  and  applied  to  the  skin.  Mustard  and  other  remedies  may  be  added 
to  the  poultice  in  order  to  induce  special  effects,  and  in  some  cases  a  poultice 
consists  merely  of  drugs  enclosed  in  a  cloth  sack,  as  in  charcoal  or  spice 
poultices. 

Enemata,  clysmata,  or  clysters,  are  liquid  substances  injected  into  the  rec- 
tum for  their  local  or  general  effects.  (See  page  31.) 

CLASSIFICATION  OF  DRUGS. 

Vriters  on  pharmacology  and  therapeutics  arrange  drugs  on  many  differ- 
ent principles.  Thus  a  somewhat  antiquated  system  classifies  the  vegetable 
remedies  according  to  the  botanical  families  from  which  they  are  obtained, 
but  there  is  little  advantage  in  this  arrangement,  for  an  order  may  include 
drugs  which  differ  entirely  in  their  action  and  in  the  therapeutic  uses  to 
which  they  are  put,  while,  on  the  other  hand,  two  widely  separated  botanical 
groups  may  contain  identical  poisons.  Another  classification  of  drugs  is 
according  to  their  therapeutic  effects,  and  this  might  seem  at  first  sight  the 
most  convenient  for  students  of  medicine.  This  plan  has  its  drawbacks, 
however,  for  many  drugs  are  used  for  a  large  number  of  different  purposes, 
and  it  is  impossible  to  describe  them  under  each  heading.  In  addition,  the 
classification  in  groups  is  always  liable  to  suggest  a  much  closer  resemblance 
in  the  effects  of  the  individual  drugs  than  really  exists.  Thus  the  drugs 
often  classed  as  " cardiac  stimulants"  differ  much,  not  only  in  their  effects 
on  the  body  in  general,  but  in  their  action  on  the  heart,  and  opinions  may 
differ  as  to  whether  some  of  them  stimulate  or  depress  the  heart.  They 
certainly  cannot  be  substituted  for  each  other  in  the  treatment  of  heart  dis- 
ease, as  is  suggested  by  their  being  classified  together  under  this  heading. 
Finally,  practical  therapeutics  can  be  taught  only  in  the  clinic,  and  in  the 
teaching  of  pharmacology  it  seems  advisable  to  direct  the  student's  attention 
rather  to  the  action  of  drugs  than  to  the  practical  uses,  which  can  be  taught 
to  much  greater  advantage  in  connection  with  the  symptoms,  prognosis,  and 
other  clinical  features  of  disease.  The  classification  of  drugs  and  poisons 
according  to  their  action  on  living  matter  is  the  natural  one,  and  is  based 
on  the  same  logical  principle  as  the  modern  classification  of  plants  in  bot- 
any and  of  animals  in  zoology.  The  object  is  to  group  together  those  sub- 
stances which  have  most  points  of  resemblance,  whether  they  are  obtained 
from  the  same  or  from  different  orders  of  plants,  and  whatever  relation 
they  may  bear  to  each  other  in  therapeutics.  This  classification,  which 
was  introduced  by  Buchheim,  has  been  further  developed  by  Schmiedeberg 
and  his  pupils.  In  the  present  state  of  knowledge  it  is  necessarily  imper- 


42  INTRODUCTION. 

feet,,  and  many  resemblances  and  affinities  have  not  gained  that  recog- 
nition which  they  will  doubtless  receive  in  the  future.  Even  in  its  pres- 
ent imperfect  form,  however,  this  classification  is  the  most  satisfactory 
one  available,  and,  unlike  the  others,  it  can  be  easily  subjected  to  such  modi- 
fications as  the  advance  of  science  renders  necessary.  If  ever  the  ideal 
classification  be  attained,  in  which  the  grouping  is  based  upon  the  chemical 
reactions  of  the  poisons  with  the  living  protoplasm,  this  natural  classification 
will  be  found  to  conform  more  easily  to  it  than  any  based  upon  origin  or 
temporary  therapeutic  uses. 

Resemblance  in  pharmacological  action  does  not  necessarily  involve  simi- 
larity in  chemical  composition,  as  has  been  already  pointed  out.  But  it  is 
found  that  in  many  instances  the  members  of  a  pharmacological  group  have 
some  general  chemical  character  which  distinguishes  them  from  others. 
Drugs  which  resemble  each  other  in  their  pharmacological  action,  are  often 
used  for  very  different  purposes  in  therapeutics,  although  this  is  much  less 
frequently  the  case  now  than  formerly.  This  is  very  generally  due  to  the 
failure  of  the  clinicians  to  observe  the  resemblance  in  the  action  of  drugs. 
As  they  become  more  familiar  with  the  results  of  animal  experiment,  they 
will  recognize  that  in  many  instances  drugs  which  they  now  regard  as  dis- 
tinct on  account  of  superficial  differences,  really  resemble  each  other  in  all 
important  points,  and  may  be  substituted  for  each  other  in  therapeutics.  In 
this  way  it  is  to  be  hoped  that  the  natural  classification  of  drugs  will  gradu- 
ally be  found  to  approach  more  closely  to  the  therapeutic.  At  the  present 
time  the  continued  use  of  the  therapeutic  classification  can  only  tend  to  delay 
this  consummation. 

In  this  volume,  the  classification  adopted  is  that  of  Buchheim  and 
Schmiedeberg,  with  some  slight  alterations  which  seemed  to  be  de- 
manded by  recent  progress.  The  drugs  are  thrown  into  a  large  num- 
ber of  groups  which  are  named  from  the  most  prominent  member,  or 
from  some  marked  property  possessed  by  all.  These  groups  are  ar- 
ranged, as  far  as  possible,  according  to  their  mutual  resemblances.  It 
has  been  found  advisable  to  retain,  for  the  most  part,  the  divisions  into 
organic  and  inorganic  drugs,  although  this  may,  perhaps,  have  to  be 
abandoned  in  the  future.  The  first  series  of  groups  of  the  organic 
materia  medica  are  possessed  of  the  common  property  of  inducing 
more  marked  local  than  general  effects,  and  these  may  therefore  be 
classified  in  one  large  subdivision.  The  second  division  of  the  organic 
drugs  is  formed  of  those  whose  pronounced  general  action  obscures 
their  local  effects,  when  these  are  not  entirely  absent.  The  first  few 
groups  of  this  division  are  formed  of  those  whose  chief  action  is  de- 
veloped on  the  central  nervous  system ;  then  follow  those  which  in- 
volve more  especially  the  peripheral  nerves,  muscles,  and  secretory  or- 
gans ;  these,  again,  pass  into  a  series  in  which  local  irritant  action  is 
associated  with  powerful  general  effects,  and  through  these  into  a  se- 
ries of  protoplasm  poisons.  The  last  series  of  organic  groups  consists 
of  those  acting  chiefly  on  the  heart  and  vessels  directly.  The  groups 
of  the  inorganic  drugs  show  less  defined  affinities,  and  are  much  more 
difficult  to  classify  than  the  organic  series.  The  salts  of  the  alkalies 
and  alkaline  earths,  the  acids  and  alkalies  may  be  thrown  into  a  large  and 
somewhat  heterogeneous  division,  which  is  easily  marked  off  from  that 
of  the  heavy  metals,  which  have  many  points  in  common  in  their  ef- 


CLASSIFICATION  OF  DRUGS.  43 

fects  in  the  organism,  as  in  their  chemical  reactions.  The  latter  divi- 
sion is  led  up  to  by  phosphorus  and  arsenic,  and  several  bodies  which 
it  is  impossible  to  classify  at  present  are  placed  between  these  and  the 
first  inorganic  division.  Another  class  is  formed  of  a  number  of  sub- 
stances which  are  either  present  in  the  normal  body,  or  are  merely  sub- 
stitutes for  normal  secretions,  and  the  final  class  is  composed  of  a  few 
preparations  which  are  used  only  for  their  mechanical  effects,  and 
which  for  the  most  part  are  not  drugs,  although  they  are  included  in 
the  pharmacopoeias. 

It  must  be  emphasized  that  no  attempt  is  made  to  draw  hard  and 
fast  lines  of  demarcation  between  the  different  groups.  The  essential 
features  of  the  natural  system  involve  the  recognition  that  this  is  im- 
possible. It  has  therefore  been  considered  best  not  to  indicate  any 
definite  point  at  which  the  discussion  of  poisons  acting  on  the  central 
nervous  system  ends  and  that  of  the  drugs  with  peripheral  effects  be- 
gins. The  student  is  always  liable  to  lay  more  importance  on  such 
divisions  than  is  intended  by  the  writer,  to  list  those  on  one  side  of 
the  dividing  line  as  central,  those  on  the  other  as  peripheral  in  action, 
whereas  the  transition  is  gradual.  The  six  chief  divisions  are  therefore 
the  only  ones  indicated. 


PART  I. 

ORGANIC  SUBSTANCES  WHICH  ARE  CHAR- 
ACTERIZED CHIEFLY  BY  THEIR 
LOCAL  ACTION. 

THIS  class  contains  a  very  considerable  part  of  the  drugs  included 
in  the  pharmacopoeias,  although  it  bears  a  smaller  proportion  than  for- 
merly to  the  other  classes.  There  is  still,  however,  in  it  a  large 
number  of  drugs  which  have  practically  identical  effects,  and  there  is 
no  question  that  it  might  be  considerably  curtailed  without  loss  to 
therapeutic  practice.  Many  of  its  members  are  irritants,  and  these 
have  been  subdivided  for  convenience  into  groups  according  to  the 
organs  on  which  they  exert  their  chief  action  and  the  purposes  for 
which  they  are  used  in  therapeutics,  as  gastric,  intestinal,  cutaneous 
irritants.  Others  act  as  protectives,  covering  injured  surfaces  (demul- 
cents, emollients),  and  still  others  precipitate  the  proteids  on  the  sur- 
faces to  which  they  are  applied  (astringents).  Others  seem  to  act 
chiefly  by  affecting  the  taste,  and  finally  a  heterogeneous  group  which 
is  used  in  the  treatment  of  intestinal  parasites,  has  been  inserted  here. 

I.    DEMULCENTS. 

A  large  number  of  colloid  substances — chiefly  gums,  dextrins,  sugars 
and  starches — owe  their  use  in  medicine,  not  to  any  changes  they  pro- 
duce in  the  cells  with  which  they  come  in  contact,  but  to  the  fact  that 
they  are  cohesive  and  serve  to  protect  surfaces  mechanically.  When 
they  are  applied  to  a  sensitive  surface,  they  retard  the  movement  of 
fluid  or  air  against  it  and  thus  preserve  it  from  the  effects  of  these 
agents.  This  may  be  illustrated  by  familiar  examples  in  which  the 
taste  of  food  is  altered  by  their  presence,  although  they  have  often  no 
taste  or  odor  in  themselves.  Sugar  dissolved  in  mucilage  tastes  less 
sweet  than  in  water,  and  acids  are  also  less  appreciated,  as  may  be  ob- 
served in  many  fruits.  For  example,  the  raspberry  contains  more  acid 
and  less  sugar  than  the  currant,  but  in  the  former  the  acid  taste  is  con- 
cealed by  the  presence  of  large  quantities  of  colloids,  so  that  the  rasp- 
berry is  regarded  as  a  sweet  fruit,  the  currant  as  an  acid  one.  Even 
cold  is  felt  less  when  a  colloid  substance  is  present  in  the  fluid  swal- 
lowed ;  thus,  ice-cream  or  iced  milk  does  not  feel  so  cold  on  the  tongue 
and  throat  as  frozen  water,  because  the  colloid  proteid  substances  form 
a  protecting  layer  over  the  surface,  and  prevent  the  cold  mass  from 
reaching  the  sensory  terminations  so  freely  as  it  otherwise  would.  A 

45 


46  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

number  of  experiments  carried  out  by  Tappeiner1  show  that  other 
organs  may  be  protected  in  the  same  way  by  colloid  solutions.  Strong 
salt  solution  applied  to  a  motor  nerve  first  stimulates  and  then  slowly 
paralyzes  it,  but  Tappeiner  found  that  both  of  these  effects  are  much 
Jess  marked  if  the  solution  be  made  up  with  mucilage  instead  of  with 
water,  because  the  salt  does  not  reach  the  nerve  so  readily.  In  the 
same  way,  intense  pain  is  caused  in  a  wound  by  strong  salt  solution, 
but  is  much  less  severe  if  the  solution  contain  colloid  material. 

When  demulcents  reach  the  stomach,  they  appear  to  coat  the  wall 
and  thus  to  alter  the  sensation  arising  from  food,  for  Quincke  found  in 
a  case  of  gastric  fistula  that  the  patient  could  distinguish  milk  from 
water  even  when  it  was  passed  directly  into  the  stomach,  and  Pawlow 
states  that  the  presence  of  starch  in  the  stomach  alters  the  secretion 
induced  by  food.  Tappeiner  found  that  much  less  inflammation  of  the 
intestine  is  caused  by  irritants  if  they  are  suspended  in  demulcents  than 
if  they  are  dissolved  in  water ;  at  the  same  time  the  presence  of  colloid 
unabsorbable  bodies  may  increase  the  efficiency  of  purgatives  by  pre- 
venting their  absorption  in  the  upper  part  of  the  bowel.  The  digestion 
of  proteids  outside  the  body  is  retarded  by  the  presence  of  the  demul- 
cents, and  probably  this  is  also  true  of  the  process  in  the  stomach. 
Colloid  bodies  also  retard  the  absorption  of  fluids  from  the  stomach  and 
bowel,  and  this  leads  to  a  feeling  of  distention,  which  is  much  less 
marked  if  the  same  amount  of  fluid  be  swallowed  without  colloid  ;  for 
instance,  water  is  absorbed  more  rapidly  than  milk  or  beer. 

The  slow  absorption  of  colloid  fluids  allows  time  for  decomposition, 
and  this  may  give  rise  to  irritation  and  catarrh.  The  colloids  them- 
selves are  absorbed  very  slowly,  and  probably  only  in  a  condition  of 
semi-decomposition.  After  absorption,  they  are  oxidized  in  the  tissues 
and  therefore  act  as  foods  to  some  extent,  although  their  slow  absorp- 
tion prevents  their  being  of  much  value.  They  have,  of  course,  no 
effect  as  demulcents  after  absorption,  but  the  large  quantity  of  fluid 
with  which  they  are  generally  taken  may  be  of  benefit  in  some  condi- 
tions. 

Demulcents  are  used  to  cover  inflamed  surfaces ;  in  tonsillitis,  for 
example,  they  may  be  applied  as  gargles,  or  better  by  sucking  lozenges 
containing  them.  They  are  not  often  applied  externally  for  this  pur- 
pose, as  they  are  liable  to  serve  as  media  for  the  growth  of  micro- 
organisms. In  gastric  and  intestinal  catarrh  their  use  is  objectionable 
for  the  same  reason,  their  slow  absorption  leading  to  decomposition 
with  the  formation  of  irritants,  which  may  do  more  harm  than  is  coun- 
terbalanced by  their  protective  action.  Instead  of  demulcents,  some 
of  the  oils,  such  as  olive  oil  (p.  51),  have  been  recommended  as  pro- 
tectives  in  disease  of  the  stomach  and  intestine. 

In  acute  irritant  poisoning  the  demulcents  are  often  of  great  value,  as 
they  protect  the  stomach  wall  from  the  effects  of  the  poison.  The  best 
remedy  in  these  cases,  because  the  most  readily  obtainable,  is  milk  or 
white  of  eggs. 

1  Tappeiner,  Archives  internat.  d.  Pharmacodyn.,  x.,  p.  67. 


DEMULCENTS.  47 

Their  effects  in  retarding  the  absorption  of  other  remedies  may  be 
taken  advantage  of.  Thus  when  the  effect  of  alcohol  on  the  stomach 
or  bowel  is  desired,  it  is  given  as  wine,  which  contains  colloid  material, 
and  is  therefore,  absorbed  slowly ;  it  must  be  noted,  however,  that 
these  same  colloids  delay  digestion  much  more  than  alcohol  itself.  In 
the  same  way  opium  and  extract  of  nux  vomica  are  prescribed  when 
the  local  action  on  the  bowel  and  stomach  is  desired,  while  the  pure 
alkaloids,  morphine  and  strychnine,  are  administered  for  their  effects 
after  absorption. 

Demulcents  are  often  given  instead  of  pure  water  in  cases  where  it 
is  desired  to  administer  large  quantities  of  fluid,  as  they  have  more 
"  body  "  and  are  more  agreeable  to  the  taste.  Thus,  barley  water  or 
some  other  demulcent  may  be  advised  in  order  to  assuage  the  thirst 
of  fever,  or  to  dilute  the  urine  when  it  is  too  concentrated  or  too 
acid. 

Demulcents  are  often  used  as  the  basis  of  enemata  which  are  intended 
to  be  absorbed,  because  solutions  containing  colloids  are  less  irritant 
and  therefore  less  liable  to  set  up  peristalsis  than  pure  water.  For 
this  purpose  starch  solution  is  generally  used. 

Some  of  the  gums,  notably  acacia  and  tragacanth,  are  seldom  advised 
as  demulcents,  but  are  often  prescribed  in  order  to  hold  in  suspension 
in  water  such  insoluble  bodies  as  resins  and  oils,  or  to  give  cohesion  to 
pills  and  lozenges. 

PREPARATIONS. 

Acacia  (U.  S.  P.)  Acaciae  Gummi  (B.  P.)  (gum  arable),  a  gummy  exuda- 
tion obtained  from  Acacia  Senegal,  consists  of  the  potassium,  magnesium, 
and  calcium  salts  of  a  weakly  acid  substance,  arabin  or  arabinic  acid 
(C6H10O5).  It  is  soluble  in  equal  parts  of  water,  and  is  used  as  a  demulcent, 
but  more  largely  as  a  vehicle  for  other  drugs. 

MUCILAGO  ACACIA  (U.  S.  P.,  B.  P.). —About  1  part  acacia  in  2  of  water. 
Dose,  16  c.c.  (4fl.  drs.). 

Syrupus  Acacice  (U.  S.  P.). 

Tragacantha  (U.  S.  P.,  B.  P.),  a  gummy  exudation  from  various  species 
of  Astragalus,  contains  salts  of  arabin  and  tragacanthin.  Tragacanthin  differs 
from  arabin  in  not  dissolving,  but  merely  swelling  up  into  a  jelly  in  water. 
Tragacanth  is  used  chiefly  to  suspend  heavy  powders  in  water. 

MUCILAGO  TRAGACANTH^E  (U.  S.  P.,  B.  P.),  formed  of  tragacanth, 
glycerin  and  water.  In  the  B.  P.  alcohol  is  used  instead  of  glycerin.  Dose, 
16  c.c.  (4  fl.  drs.). 

Glycerinum  Tragacanthse  (B.  P.),  a  solution  of  tragacanth  in^  glycerin  and 
water. 

Pulvis  Tragacanthse  Compositus  (B.  P.),  contains  tragacanth,  gum  acacia, 
starch  and  sugar.  Dose,  20-60  grs. 

Sassafras  Medulla  (U.  S.  P.),  the  pith  of  Sassafras  variifolium  (sassafras)o 

Ulmus  (U.  S.  P.),  the  inner  bark  of  Ulmus  fulva  (slippery  elm). 

Althaea  (U.  S.  P.),  the  root  of  Althaea  officinalis  (marsh-mallow). 

Linum  (U.  S.  P.,  B.  P.),  the  seed  of  Linum  usitatissimum  (linseed). 

Linum  Contusum  (B.  P.),  crushed  linseed. 

Mucilago  Sassafras  Medulla  (U.  S.  P.).     Dose,  16  c.c.  (4  fl.  drs.). 

Mucilago  Ulmi  (U.  S.  P.).     Dose,  16  c.c.  (4  fl.  drs.). 

These  all  contain  colloid  substances  which  are  extracted  with  hot  water,  and 
which  are  believed  to  be  nearly  related  to  arabin.  They  are  largely  used  in 


48  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

domestic  medicine  as  demulcents  in  sore  throat,  and  may  be  prescribed  to  sus- 
pend powders  or  oils.     The  syrup  of  marsh-mallow  is  a  pleasant  flavor. 

Triticum  (U.  S.  P.),  the  rhizome  of  Agropyrum  repens,  or  couch-grass, 
contains  mannite,  laBvulose,  and  a  starchy  substance,  triticin.  Its  decoction 
is  used  as  a  beverage  in  fever,  and  to  dilute  the  urine.  It  has  a  certain 
popular  reputation  as  a  diuretic  in  suppression  of  the  urine,  calculus,  etc. , 
but  this  is  entirely  unmerited,  for  it  increases  the  urine  simply  by  the  water 
given  with  it. 

Amylum  (U.  S.  P.,  B.  P.),  or  starch,  may  be  formed  into  a  jelly  by  boiling 
in  water,  and  may  then  be  used  for  the  same  purpose  as  the  demulcents. 

Glyceritum  Amyli  (U.  S.  P.),  Glycerinum,  Amyli  (B.  P.),  is  a  jelly  formed 
by  heating  starch  with  water  and  glycerin. 

Amygdala  Dulcis  (U.  S.  P.,  B.  P.),  or  sweet  almonds,  the  seed  of  Prunus 
amygdala  dulcis,  contains  a  fixed  oil  and  emulsin,  a  ferment,  but,  unlike  the 
bitter  almond,  no  amygdalin.  When  triturated  with  water  it  forms  an 
emulsion,  or  mixture,  which  is  bland  and  demulcent. 

Emulsum  Amygdala  (U.  S.  P.),  Mistura  Amygdala  (B.  P.).  Dose,  120  c.c. 
.  (4  fl.  oz.). 

Pulvis  Amygdalse  Compositus  (B.  P.)  contains  sugar  and  acacia  with  almond. 

Syrupus  Amygdalae  (U.  S.  P.)  is  formed  from  a  mixture  of  sweet  and  bitter 
almonds,  and  therefore  contains  a  small  proportion  of  prussic  acid,  but  may 
be  used  in  the  same  way  as  the  demulcents  with  perfect  safety. 

Glycyrrhiza  (U.  S.  P.),  Glycyrrhizae  Radix  (B.  P.),  or  liquorice-root, 
the  root  of  Glycyrrhiza  glabra  (var.  glandulifera),  is  used  as  a  demulcent, 
and  more  largely  to  flavor  medicines.  It  has  a  pleasant,  sweet  taste,  owing 
to  the  presence  of  Glycyrrhizin,  an  acid  glucoside,  which  is  combined  with 
calcium  and  ammonia  in  the  plant,  and  is  not  soluble  in  cold  water,  but  swells 
up  in  it  to  a  jelly-like  mass.  Glycyrrhizin  is  probably  decomposed  in  the 
body  ;  the  urine  is  often  found  to  contain  a  reducing  body  after  the  admin- 
istration of  liquorice. 

EXTRACTUM  GLYCYRRHIZA  (U.  S.  P..  B.  P.).     Dose,  1  G.  (15  grs.). 

Extractum  Glycyrrhizce  Purum  (U.  S.  P.).     Dose,  1  G.  (15  grs.). 

Fluidextractum  Glycyrrhizce  (U.  S.  P.),  Extractum  Glycyrrhizce  Liquidum 
(B.  P.).  Dose,  2  c.c.  (30  mins.). 

Glycyrrhizinum  Ammoniatum  (U.  S.  P.),  the  ammonium  salt  of  glycyrrhizin. 

PULVIS  GLYCYRRHIZA  COMPOSITUS  (U.  S.  P.,  B.  P.)  contains  senna. 
Dose,  2-8  G.  (30-120  grs.). 

TROCHISCI  GLYCYRRHIZA  ET  OPII  (U.  S.  P.). 

MISTURA  GLYCYRRHIZAE  COMPOSITA  (U.  S.  P.),  "  Brown  Mixture,"  con- 
tains opium,  antimony  and  spirits  of  nitrous  ether.  Dose,  15-30  c.c.  (1-2 
tablespoonfuls). 

The  extract  is  largely  used  in  the  form  of  lozenges  for  its  demulcent  ac- 
tion, and  is  very  frequently  used  to  make  up  pills.  It  is  slightly  laxative, 
and  may  be  used  as  a  pleasant  aperient  for  children  ;  the  compound  powder 
is  more  reliable  for  this  purpose  owing  to  its  containing  senna,  one  of  the 
vegetable  purgatives. 

The  lozenges  and  the  brown  mixture  contain  opium  and  are  used  largely 
in  cough  and  in  catarrh  of  the  air  passages. 

Numbers  of  other  substances  are  used  as  demulcents  in  domestic  medi- 
cine, and  are  found  in  different  pharmacopoeias.  Examples  of  these  are 
barley  (Hordeum),  salep,  verbascum  and  quince  seeds.  Iceland  moss  is  a 
lichen  (Cetraria  islandica),  and  contains  starch  bodies  together  with  acids,  which 
can  be  removed  by  soaking  in  dilute  alkaline  solutions  for  some  time. 

Chondrus  (U.  S.  P.)  (Irish  moss  or  Carragheen),  Chondrus  crispus,  a  seaweed 
gathered  on  the  coasts  of  Ireland  and  Massachusetts.  Chondrus  contains  a 
carbohydrate,  carrageenin.  The  decoction  forms  a  jelly  when  cold,  and  was 
formerly  supposed  to  form  a  valuable  food  in  illness,  but  it  is  of  little  value  for 
this  purpose,  for  only  about  ^V'sV  of  the  jelly  is  solid  matter,  the  rest  water. 


EMOLLIENTS.  49 


II.    EMOLLIENTS. 

Emollients  are  bland,  oily  substances  which  are  applied  to  the 
skin  to  protect  it  from  irritation,  and  to  render  it  softer  and  more 
elastic,  and  thus  bear  the  same  relation  to  the  skin  as  the  demulcents 
to  the  mucous  membranes.  Their  effect  in  rendering  the  skin  softer 
and  more  pliable  may  be  due  in  part  to  their  penetration  into  the 
surface  layers,  but  may  also  be  explained  by  the  slight  congestion 
induced  by  the  rubbing  and  massage  used  in  their  application. 

The  older  emollients  were  chiefly  animal  and  vegetable  fats  and 
oils,  but  several  newer  drugs  of  this  class  are  derived  from  petroleum. 
The  effects  of  these  drugs  when  applied  to  the  skin  are  purely  local. 
No  doubt  some  small  percentage  is  absorbed  into  the  tissues,  but  this 
has  no  known  effect  in  man,  and  although  the  fats  and  oils  are  valu- 
able foods  when  taken  internally,  this  plays  no  part  in  their  effects 
when  applied  to  the  skin. 

The  emollient  preparations  promote  the  absorption  of  drugs  dis- 
solved in  them,  because  they  mix  readily  with  the  thin  layer  of  oily 
sebaceous  matter  which  covers  the  epithelium.  The  active  substances 
dissolved  in  them  therefore  come  into  intimate  contact  with  the  absorb- 
ing cells  lining  the  ducts  of  the  glands,  while  watery  solutions  are 
separated  from  the  lining  cells  by  a  layer  of  sebum.  If  this  layer  be 
dissolved  off  by  alcohol,  watery  solutions  are  also  absorbed  rapidly, 
and  alcoholic  solutions  are  absorbed  as  quickly  as  oily  solutions,  be- 
cause the  alcohol  is  miscible  with  the  sebum.  On  the  other  hand 
solutions  in  water  come  into  more  intimate  contact  with  the  cells  of  the 
mucous  membranes  and  with  the  subcutaneous  tissues,  and  are  there- 
fore more  readily  absorbed  by  these  than  oily  solutions.  To  ensure 
rapid  absorption,  a  drug  should  be  dissolved  in  some  emollient  if  it  is 
to  be  absorbed  by  the  skin,  in  water  when  it  is  to  be  administered 
internally  or  hypodermically.  Solutions  in  oil  of  such  antiseptics  as 
carbolic  acid  are  much  less  powerful  than  those  in  water,  because  car- 
bolic acid  being  more  soluble  in  oil  fails  to  diffuse  into  the  watery  proto- 
plasm of  the  microbe,  for  which  it  has  less  affinity.  (See  Antiseptics 
of  the  Benzol  Series.)  But  antiseptics  which  are  more  soluble  in  water 
than  in  oils  are  said  to  be  equally  active  in  both  solvents. 

The  emollients  are  applied  as  protectives  in  abrasions,  cuts,  bruises, 
chapped  hands,  burns ;  they  are  less  often  used  alone  in  extensive  skin 
diseases,  but  are  usually  prescribed  in  these  as  the  basis  of  ointments 
in  which  other  remedies  are  incorporated.  There  is  no  question  that 
the  protection  afforded  to  the  part  and  the  exclusion  of  the  air  by 
the  oily  emollient  plays  an  important  part  in  the  action  of  these  reme- 
dies, and  it  seems  probable  that  in  many  cases  equally  good  results 
would  follow  the  application  of  the  emollient  without  any  active 
ingredient. 


50  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

PREPARATIONS. 

Adeps  (U.  S.  P.,  B.  P.),  lard ;  the  prepared  internal  fat  of  the  abdomen 
of  the  pig,  purified  by  washing  in  water,  melting  and  straining. 

Adeps  Benzoinatus  (U.  S.  P.),  Adeps  Benzoatus  (B.  P.),  benzoinated  lard,  is 
prepared  from  lard  by  the  addition  of  benzoin,  which  is  slightly  antiseptic 
and  preserves  it  from  becoming  rancid, 

UNGUENTUM  (U.  S.  P.),  ointment,  is  a  mixture  of  lard  and  yellow  wax. 
It  was  formerly  known  as  Unguentum  Simplex,  and  is  the  basis  of  many 
other  ointments. 

Unguentum  Diachylon  (U.  S.  P.)  is  formed  from  lead  plaster  and  olive  oil, 
perfumed  with  oil  of  lavender.  The  lead  is  inert,  the  action  being  identical 
with  that  of  ordinary  ointment. 

UNGUENTUM  AQU^:  Ros^:  (U.  S.  P.,  B.  P.),  cold  cream,  is  formed  of  sper- 
maceti, white  wax,  oil  of  almonds,  and  some  borax,  scented  with  rose  water. 

Sevum  Praeparatum  (U.  S.  P.,  B.  P.),  mutton  suet,  is  obtained  from  the 
abdominal  fat  of  the  sheep. 

Lard  and  suet  have  the  ordinary  constituents  of  animal  fats,  stearin,  pal- 
mitin-  and  olein.  They  are  seldom  used  alone,  but  form  the  basis  of  numer- 
ous ointments.  These  animal  fats  tend  to  putrefy,  and  are  then  rendered 
irritant  by  the  presence  of  free  acids  (rancidity),  and  have  therefore  been 
replaced  to  a  considerable  extent  of  late  years  by  other  preparations  which 
do  not  suffer  from  this  drawback. 

Adeps  Lanae  Hydrosus  (U.  S.  P.,  B.  P.),  hydrous  wool-fat,  lanolin,  the 
purified  fat  of  sheep-wool,  mixed  with  not  more  than  30  per  cent,  of  water. 

Adeps  Lance  (U.  S.  P.,  B.  P.),  wool-fat  without  water. 

Lanolin  has  been  used  extensively  in  medicine  only  in  the  last  few  years. 
It  consists  of  cholesterin  esters  with  some  impurities,  does  not  become  ran- 
cid, and  differs  from  the  older  fats  also  in  being  miscible  in  twice  its  weight 
of  water  without  losing  its  ointment  consistency.  Lanolin  is  very  often  used 
as  an  emollient  application,  as  well  as  to  form  a  basis  for  more  active  drugs. 

Other  preparations  of  wool-fats  are  known  as  lanichol  and  alapurin. 

Petrolates  or  Paraffins.  When  the  more  volatile  constituents  of  petroleum 
are  distilled  off,  there  remain  a  number  of  higher  hydrocarbons,  chiefly  of 
the  marsh  gas  series,  which  are  used  in  medicine  as  emollients.  The  lower 
of  these  hydrocarbons  are  fluid  at  ordinary  temperatures  and  are  known  as 

Petrolatum  Liquidum  (U.  S.  P.),  Paraffinum  Liquidum  (B.  P.),  a  colorless, 
oily  transparent  liquid  without  odor  or  taste.  When  these  are  removed 
there  remains 

PETROLATUM  (U.  S.  P.)  and  PETROLATUM  ALBUM  (U.  S.  P.),  PARAFFINUM 
MOLLE  (B.  P.),  soft  petrolate,  vaselin,  which  has  the  consistency  of  an  oint- 
ment, is  yellow  or  white  in  color,  and  is  liquefied  a  few  degrees  above  the  tem- 
perature of  the  blood.  When  the  distillation  is  carried  further,  the  residue  is 
solid  at  ordinary  temperatures,  and  is  known  as 

Paraffinum  (U.  S.  P.),  Paraffinum  Durum  (B.  P.),  or  hard  paraffin,  which 
melts  at  a  somewhat  higher  temperature  than  vaselin. 

Unguentum  Paraffini  (B.  P.)  is  a  mixture  of  three  parts  of  hard  paraffin 
with  seven  parts  of  vaselin. 

By  mixing  the  petrolates  a  salve  of  any  desired  consistency  may  be  ob- 
tained. Soft  petrolate  is  often  known  as  petrolatum,  as  it  is  much  more 
extensively  used  than  the  others.  It  is  used  as  an  emollient,  and  as  a  basis 
for  ointments  and  has  the  advantage  over  the  older  lard  and  suet  that  it 
does  not  become  rancid.  Liquid  vaselin  has  been  used  to  dissolve  irritant 
substances  for  subcutaneous  injection,  as  much  less  pain  is  caused  when  they 
are  dissolved  in  vaselin  than  when  water  is  used.  Sobieranski l  has  shown 
that  vaselin  rubbed  into  the  skin  is  absorbed  to  some  extent,  and  may  be 
recovered  from  the  muscles  and  to  a  less  extent  from  other  organs,  Babbits 

329f 


^       J_l_HAOV^J.\^0       C4-J.AV1.        UVy     C*     AV^OQ      V^A.WU.11       J.AV/JJJ.       ' 

1  Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi.,  p. 


EMOLLIENTS.  51 

lost  flesh  and  some  of  them  died  under  the  continued  application  of  vaselin, 
but  this  may  have  been  due  to  the  manipulation  and  not  to  the  drug  itself. 

Several  Oils  are  also  used  as  emollients. 

Oleum  Olivse  (U.  S.  P.,  B.  P.),  olive  oil,  a  fixed  oil  obtained  from  the  ripe 
fruit  of  the  olive,  Olea  europsea. 

Oleum  Lini  (U.  S.  P.,  B.  P.),  Linseed  or  Flaxseed  oil. 

Oleum  Amygdalss  Expressum  (U.  S.  P.),  Oleum  Amygdalae  (B.  P.),  a  fixed 
oil  expressed  from  bitter  or  sweet  almonds.  It  is  to  be  distinguished  from 
the  volatile  oil  obtained  from  the  bitter  almonds.  The  fixed  oil  contains  no 
prussic  acid. 

Oleum  Gossypii  Seminis  (U.  S.  P.),  Cotton-seed  oil. 

Oleum  Adipis  (U.  S.  P.),  oil  of  lard. 

These  all  resemble  each  other  in  their  composition,  and  may  be  used  as 
emollients.  Olive  oil  is  generally  preferred  to  the  others,  but  is  much  more 
expensive,  and  it  is  probable  that  much  of  the  so-called  olive  oil  is  really 
purified  cotton-seed  oil.  Olive  oil  has  been  advised  as  a  cholagogue,  but  has 
been  shown  by  more  exact  methods  of  research  to  have  no  effect  whatever 
on  the  secretion  of  the  bile.  It  sometimes  gives  relief  in  biliary  colic  and  dys- 
entery and  in  some  gastric  disorders  accompanied  by  pyloric  spasm,  probably 
from  its  acting  as  a  protective  to  the  mucous  membrane  of  the  stomach  and  duo- 
denum. A  wineglassful  is  given  two  or  three  times  a  day  before  meals  ;  in  these 
large  doses  it  possesses  a  high  food- value.1 

Cera  Flava  (U.  S.  P.,  B.  P.),  yellow  wax. 

Cera  Alba  (U.  S.  P.,  B.  P.),  white  wax  prepared  from  the  yellow  by 
bleaching. 

Cetaceum  (U.  S.  P.,  B.  P.),  spermaceti,  obtained  from  the  cachelot  (Phys- 
eter  macrocephalus),  one  of  the  \vhales. 

These  three  preparations  are  not  used  alone,  but  are  often  added  to  the 
emollients  and  ointments  in  order  to  give  them  a  firmer  consistency,  which 
is  especially  desirable  in  hot  climates  and  in  summer. 

Ceratum  (U.  S.  P.)  a  mixture  of  3  parts  of  wax  with  7  of  lard. 

Unyuentum  Cetacei  (B.  P. )  is  a  mixture  of  white  wax  and  spermaceti  and  olive 
or  almond  oil. 

GLYCERIXUM  (U.  S.  P.,  B.  P.),  Glycerin,  a  liquid  obtained  by  the  decom- 
position of  animal  or  vegetable  fats  or  fixed  oils,  and  containing  not  less  than 
95  per  cent,  of  absolute  glycerin,  C3H5(OH)3 ;  clear,  colorless,  of  a  syrupy 
consistence,  oily  to  the  touch,  with  a  sweet  taste  and  no  odor,  soluble  in 
water  and  alcohol. 

Glyceritum  Amyll  (U.  S.  P.),  Glycerinum  Amyli  (B.  P.),  glycerite  of  starch. 

Glyceritum  Vitelli  (U.  S.  P.),  glyconin,  glycerite  of  yolk  of  eggs,  may  be 
used  as  a  protective,  but  is  more  largely  prescribed  to  form  emulsions. 

Glycerin  is  used  as  a  solvent  for  a  number  of  other  drugs,  the  prepara- 
tions being  known  as  glycerites  (U.  S.  P.),  glycerines  (B.  P.). 

Glycerin  is  somewhat  irritant  to  the  unbroken  skin,  when  it  is  ap- 
plied in  the  pure  form,  and  even  diluted  glycerin  causes  pain  and 
smarting  when  it  is  applied  to  unprotected  surfaces  such  as  cuts  or 
burns,  but  the  pain  soon  disappears,  and  glycerin  then  acts  as  a  pro- 
tective. The  irritation  is  due  to  the  glycerin  abstracting  the  fluids  of 
the  tissues  owing  to  its  avidity  for  water.  Glycerin  and  its  prepara- 
tions are  used  very  extensively  as  applications  to  slight  wounds,  in  ir- 
ritation of  the  skin  and  lips  from  exposure  to  cold,  and  in  similar  con- 
ditions. They  are  often  applied  to  hard,  dry  crusts  on  the  skin  in 
order  to  soften  them  and  permit  of  their  removal. 

1  Cohnheim,  Ztschr.  f.  klin.  Me.d,  lii.,  p.  110. 


52  ORGANIC  SUBSTANCES  ACTING  LOYALLY. 

The  irritant  action  of  glycerin  causes  peristalsis  and  evacuation  of 
the  bowels  when  small  quantities  are  injected  into  the  rectum ;  the 
stool  is  of  almost  ordinary  consistency,  and  no  pain  or  colic  is  felt 
subsequently,  nor  does  the  remedy  cause  more  than  one  evacuation. 
Glycerin  may  be  injected  into  the  rectum  for  this  purpose  (dose  2-5  c.c., 
J-l  teaspoonful),  but  a  more  convenient  form  is  the  glycerin  supposi- 
tories, Suppositoria  Glycerin!,  which  are  made  up  with  stearic  acid 
and  sodium  carbonate,  U.  S.  P.,  with  gelatin,  B.  P.  These  suppositories 
are  found  not  to  keep  well,  as  the  glycerin  tends  to  attract  moisture 
and  then  escapes  ;  to  avoid  this  they  are  often  encased  in  paraffin,  which 
is  broken  off  immediately  before  they  are  inserted.  Glycerin  sup- 
positories are  used  in  constipation  instead  of  the  ordinary  aperients, 
and  they  have  also  been  advised  in  parturition  to  increase  the  pains. 
Large  doses  of  glycerin  taken  internally  sometimes  cause  purgation, 
but  it  is  not  a  reliable  remedy  when  administered  in  this  way. 

Glycerin  in  large  quantities  is  poisonous  whether  it  is  taken  by  the  mouth 
or  injected  hypodermically  or  intravenously.  It  is  true  that  no  case  of 
glycerin  poisoning  in  man  is  known,  but  large  doses  are  fatal  to  animals  in 
the  course  of  a  few  hours.  The  chief  symptoms  are  restlessness,  agitation, 
acceleration  of  the  heart  and  respiration,  general  weakness,  tremor  and 
convulsions,  which  finally  end  in  somnolence,  coma,  and  death  from  failure 
of  the  respiration.  The  convulsions  are  marked  only  after  large  doses, 
when  they  may  assume  a  tetanic  character.  A  rise  in  the  temperature  has 
been  noted  by  several  observers,  followed  by  a  fall  which  continues  until 
death.  When  glycerin  is  injected  subcutaneously  in  large  quantities, 
haemoglobin  appears  in  the  urine,  while  this  is  rarer  when  it  is  given  by  the 
mouth,  and  scarcely  ever  occurs  after  intravenous  injection.  This  is  ob- 
viously due  to  the  destruction  of  the  red  blood  cells,  but  glycerin  added  to 
the  drawn  blood  does  not  act  so  strongly  on  it  as  many  other  bodies  which 
cause  no  hsemoglobinuria.  Filehne  explains  the  appearance  of  haemoglobin 
in  the  urine  after  the  subcutaneous  injection  of  glycerin  by  supposing  that 
the  glycerin  remains  outside  the  vessels  for  some  time,  and  withdraws  the 
fluid  from  the  red  cells  as  they  pass  through  the  poisoned  zone.  As  the  cells 
return  into  the  larger  vessels,  they  take  up  fluid  again  and  give  off 
hemoglobin.  On  the  other  hand,  when  glycerin  is  injected  into  the  blood, 
it  diffuses  rapidly  all  over  the  body,  and  the  blood  cells  are  less  acted  on  by 
the  diluted  poison  and  do  not  alternately  shrink  and  swell  in  size.  In  addition 
to  its  action  on  the  blood  cells,  glycerin  apparently  acts  directly  on  the  central 
nervous  system,  as  is  shown  by  the  violent  convulsions.  Glomerulonephritis  has 
also  been  observed  in  animals.  Glycerin  is  absorbed  rapidly  from  the  intestine, 
and  undergoes  combustion  in  the  tissues,  only  a  very  small  fraction  of  it  reap- 
pearing in  the  urine.  Some  authors  describe  a  reducing  substance  in  the  urine 
after  the  ingestion  of  glycerin,  but  this  has  not  been  confirmed  on  more  careful 
investigation. 

It  follows  from  the  fact  that  glycerin  is  oxidized  in  the  tissues  that  ifc  must 
supply  the  body  with  energy  and  act  in  some  sense  as  a  food.  This  is  of 
interest  chiefly  because,  the  ordinary  fats  being  compounds  of  glycerin,  a 
certain  amount  must  be  contained  in  the  food,  but  it  is  also  of  some  thera- 
peutic importance,  because  glycerin  has  been  advised  as  a  food  in  inanition, 
and  has  even  been  said  to  rival  cod-liver  oil.  In  respect  to  its  value  as  a 
food,  glycerin  resembles  ordinary  alcohol,  being  readily  absorbed,  and  un- 
doubtedly increasing  the  total  energy  of  the  body.  But  it  is  still  undecided 


EMOLLIENTS.  53 

how  far  it  leads  to  an  economy  of  the  nitrogenous  tissues,  as  the  fats  and 
carbohydrates  do.  Its  combustion  saves  a  certain  amount  of  the  fat  of  the 
body  from  being  destroyed,  but  glycerin  tends  to  increase  the  non-nitrogen- 
ous, and  not  the  nitrogenous  reserve  of  the  body,  and  is  therefore  of  only 
secondary  importance  as  a  food,  although,  like  alcohol,  it  may  be  of  value 
under  certain  conditions. 

Glycerin  has  been  said  to  have  some  effect  on  the  sugar  formation  in  the 
tissues.  In  some  forms  of  experimental  glycosuria,  apparently  less  sugar  is 
found  in  the  urine  if  glycerin  be  administered,  and  in  a  certain  number  of 
cases  of  diabetes  in  the  human  subject,  some  improvement  is  said  to  have 
occurred  under  glycerin  treatment.  No  satisfactory  explanation  of  this 
point  has  been  offered.  Quite  apart  from  its  supposed  action  on  diabetes, 
glycerin  has  been  used  as  a  substitute  for  sugar  in  this  disease,  but  its  place 
has  been  taken  of  late  years  by  saccharin. 

Glycerin  has  been  shown  to  possess  some  virtue  as  an  antiseptic,  probably 
from  its  withdrawing  water  from  the  microbes,  but  like  the  oils  (page  48)  it 
is  a  less  suitable  solvent  for  many  antiseptics  than  water. 

BIBLIOGRAPHY  OF  GLYCEEIN. 

Dujardin-Beaumetz  and  Audiye.     Bull,  de  Therap.,  xci.,  p.  51. 

Plosz.     Pfliiger's  Arch.,  xvi.,  p.  153. 

Ransom.     Journ.  of  Phys.,  viii.,  p.  99. 

Schwahn.     Eckhard's  Beitrage  zur  Anatomie  und  Physiolog.,  viii.,  p.  167. 

Filehne.     Virchow's  Arch.,  cxvii.,  p.  413. 

Munk.    Virchow's  Arch.,  Ixxvi.,  p.  119  ;  Pfluger's  Arch.,  xlvi.,  p.  303. 

Arnschink.     Zeitschr.  f.  Biol.,  xxiii.,  p.  413. 

Christomanos.     Virchow's  Arch.,  clvi.,  p.  582. 

Wunschheim.     Arch.  f.  Hygiene,  xxxix,  p.  101. 

Along  with  the  emollients,  or  oily  protectives,  may  be  mentioned 
another  class  of  mechanical  agents,  the  Dusting  Powders.  Any  dry, 
insoluble,  fine  powder  applied  to  irritated  surfaces  of  the  skin,  or 
slight  abrasions,  will  protect  these  from  the  air,  and  from  contact  with 
the  clothes  and  other  sources  of  pressure.  These  powders,  at  the  same 
time,  soak  up  any  secretions,  and  render  the  injured  spot  less  liable  to 
bacterial  infection,  as  they  form  a  more  or  less  impermeable  crust. 
Powders  used  for  this  purpose  should  not  be  absorbed,  or,  if  absorb- 
able,  should  not  induce  any  toxic  effects.  Those  most  commonly  em- 
ployed are  the  phosphate  and  carbonate  of  lime,  talc  (Talcum,  Talcum 
Purificatum,  U.  S.  P.),  (magnesium  silicate),  fullers'  earth  and  kaolin 
(aluminum  silicates),  starch,  and  Lycopodium  (U.  S.  P.),  which  con- 
sists of  the  spores  of  Lycopodium  clavatum  (club  moss). 

A  large  number  of  powders  are  used  as  surgical  dressings,  most  of 
them  being  credited  with  more  or  less  antiseptic  power.  In  many  in- 
stances, however,  their  antiseptic  action  is  so  slight  that  it  would  ap- 
pear that  most  of  their  virtues  are  due  to  their  mechanical  properties, 
and  not  to  their  bactericidal  action. 


54  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

III.  SUGARS  AND  FLAVORING  SUBSTANCES. 

Sugars  are  used  in  medicine  chiefly  to  disguise  preparations  of  un- 
pleasant taste,  and  in  the  small  quantities  usually  employed  have  little 
further  effect.  In  large  quantities  sugars,  like  other  diffusible  bodies, 
act  as  irritants  to  the  stomach  and  bowel,  and  comparatively  small 
quantities  of  some  sugar  substances  possess  an  aperient  action.  Thus 
molasses  and  imperfectly  refined  sugar  have  some  reputation  in  do- 
mestic medicine  as  aperients,  and  honey,  manna,  Cassia  fistula,  and 
several  fruits  are  included  as  mild  laxatives  in  the  pharmacopoeias. 
They  are  scarcely  prescribed  alone  in  medicine,  but  are  used  to  give 
bulk  to  preparations  of  the  stronger  purgatives,  such  as  senna.  Their 
aperient  action  seems  to  be  due  to  their  colloid  form,  as  pure  sugar  has 
no  such  effect,  and  it  is  possible  that  they  merely  delay  the  absorption 
of  fluid,  and  thus  cause  softer  evacuations  than  would  otherwise  occur. 

PREPARATIONS. 

Saccharum  (U.  S.  P.),  Saccharum  Purification  (B.  P.),  cane  sugar. 

SYRUPUS  (U.  S.  P.,  B.  P.),  a  concentrated  solution  of  sugar.  Syrup  is  the 
basis  of  a  large  number  of  medicated,  syrups  of  the  pharmacopoeias.  Sugar 
and  syrup  are  used  exclusively  to  sweeten  mixtures  and  to  aid  in  the  suspen- 
sion of  insoluble  bodies.  In  place  of  ordinary  syrup  many  of  the  flavored  prep- 
arations may  be  used,  such  as  syrup  of  citric  acid,  of  acacia,  of  almonds,  etc. 

Saccharum  Lactis  (U.  S.  P.,  B.  P.),  sugar  of  milk,  lactose,  is  not  so  sweet 
as  ordinary  sugar,  and  is  much  less  liable  to  deliquesce,  so  that  it  is  used 
largely  to  give  bulk  to  powders.  It  has  been  said  to  have  diuretic  properties 
when  given  with  large  quantities  of  water,  and  to  cause  purgation  when 
given  in  a  more  concentrated  solution.  Asses'  milk  contains  more  lactose 
than  cows'  milk,  and  has  been  recommended  for  its  slight  aperient  action  in 
chronic  constipation. 

Maltum  (U.  S.  P.),  malt,  barley  grain  partially  germinated  and  then  dried. 

Extractum  Haiti  (U.  S.  P.).     Dose,  16  c.c.  (4  fl.  drs.). 

Mel,  honey,  and  Mel Depuratum  (U.  S.  P.,  B.  P. ),  or  clarified  honey,  are  used  to 
give  taste  to  mixtures,  and  have  a  very  slight  aperient  action,  so  that  they  may 
be  advised  as  articles  of  diet  in  habitual  constipation.  Some  medicated  honeys 
are  used,  of  which  Mel  ROSCR  is  included  in  the  U.  S.  P. ,  Mel  Boracis  in  the  B.  P. 

Oxymel  (B.  P.)  is  a  mixture  of  honey  and  acetic  acid.     Dose,  1—2  fl.  drs. 

Syrupus  Glucosi  (B.  P.),  a  mixture  of  liquid  glucose  and  syrup. 

Manna  (U.  S.  P.),  a  saccharine  exudation  of  Fraxinus  ornus  (Flowering 
Ash),  contains  about  50-75  per  cent,  of  mannite,  C6HH(OH)6,  a  hexatomic 
alcohol  of  sweetish,  sugary  taste.  It  has  slight  aperient  properties  when 
taken  in  large  quantities. 

Cassia  Fistula  (U.  S.  P.),  purging  Cassia,  the  fruit  of  Cassia  fistula. 

The  pulp,  Cassiae  Pulpa  (B.  P.),  contains  considerable  quantities  of  sugar. 

Tamarindus  (U.  S.  P.,  B.  P.),  tamarinds  ;  Ficus  (U.  S.  P.,  B.  P.),  figs  ; 
Prunum  (U.  S  P.,  B.  P.),  prunes,  all  contain  sugar  in  considerable  quantity. 

These  are  used  as  mild  aperients  and  flavoring  agents,  generally  in  combi- 
nation with  more  powerful  remedies.  Thus  manna  is  used  in  Infusum 
Sennse  Co.  (U.  S.  P.),  and  the  others  form  ingredients  of  Confectio 
Sennse.  They  are  not  prescribed  alone,  but  the  fruits  may  be  advised  as 
articles  of  diet  where  a  mild  laxative  is  required.  The  tamarind  pulp  may 
owe  its  aperient  action  in  part  to  the  presence  of  tartrates,  citrates,  malates 
and  other  cathartic  salts.  (See  Saline  Cathartics.) 


SIMPLE  BITTERS.  55 

Frequently  other  flavors  are  preferred  to  sugar,  which  is  especially 
disliked  in  fever  cases,  as  sweet  fluids  do  not  quench  the  thirst  so  eifect- 
ually  as  acids  and  bitters.  Many  of  the  preparations  of  the  volatile 
oils  and  some  of  the  demulcents  are  used  almost  exclusively  as  flavor- 
ing agents,  and  in  some  both  sugar  and  volatile  oil  are  combined,  as  in 
the  syrups. 

Instead  of  sugar  some  artificial  compounds  have  been  introduced  of 
late  years.  Glusidum  (B.  P.),  Benzosulphinidum  (U.  S.  P.),  or  Saccharin, 

C6H,  \  gQ  )>  NH,  and  its  sodium  salt,  C6H4  \  ^  /  N  Na,  or  soluble 

saccharin,  are  the  best  known  of  these.  Saccharin  is  a  light,  white 
crystalline  powder,  soluble  in  400  parts  of  water  and  in  25  parts  of 
alcohol.  It  is  about  500  times  as  sweet  as  sugar,  and  gives  a  distinct 
flavor  to  70,000  times  its  weight  of  water.  Dulcin,  another  aromatic 
compound,  is  said  to  be  even  sweeter  than  saccharin.  None  of  these 
tastes  exactly  like  sugar,  however,  there  being  a  distinct  flavor  besides 
that  of  sweetness,  and  patients  generally  object  to  them  after  a  short 
time.  They  have  been  used  as  substitutes  for  sugar  in  diabetes,  a  dis- 
ease in  which  sugar  is  to  be  avoided  as  far  as  possible.  Some  writers  state 
that  in  the  presence  of  saccharin  the  digestive  ferments  act  more  slowly 
than  usual,  but  the  retardation  is  only  trifling  and  does  not  preclude 
the  use  of  saccharin  in  the  small  quantities  necessary  to  sweeten  the 
food.  Like  the  other  derivatives  of  benzol,  saccharin  has  some  anti- 
septic action  and  tends  to  lessen  the  putrefaction  of  the  intestinal  con- 
tents. Even  very  large  doses  of  saccharin  may  be  injected  intrave- 
nously in  animals  without  other  effect  than  some  depression  and  stupor. 

Some  pharmacopceial  preparations  are  designed  to  give  color  to  solutions, 
but  are  seldom  or  never  prescribed,  although  they  are  sometimes  added  by 
the  pharmacist. 

Coccus  (U.  S.  P.,  B.  P.),  cochineal,  the  dried  female  of  Coccus  Cacti. 

Tinctura  Cocci  (B.  P.). 

Crocus  (B.  P.),  saffron. 

Tinctura  Croci  (B.  P.). 

Santalum  Rubrum  (U.  S.  P.),  Pterocarpi  Lignum  (B.  P.),  red  sanders, 
saunders  or  sandal  wood. 

Rhceados  Petala  (B.  P.),  the  fresh  petals  of  Papaver  Rhceas,  red  poppy. 

Syrupus  Rhoeados  (B.  P.),  i-1  fl.  dr. 

Poppy  petals  contain  none  of  the  alkaloids  of  opium. 

IV.     SIMPLE  BITTERS. 

This  group  includes  a  number  of  substances  which  have  little  in 
common  except  their  bitter  taste  and  their  comparative  inactivity  in 
the  body.  Several  alkaloids  may  be  placed  in  it,  Berberine,  Buxine, 
Menispermine  and  Canadine,  for,  although  these  are  poisonous  in  very 
large  quantities,  they  are  harmless  in  those  in  which  they  are  contained 
in  the  preparations  used  in  therapeutics.  In  addition  to  these  there 
may  be  placed  in  it  numerous  neutral  bodies,  possessing  an  intensely 
bitter  taste,  but  with  little  or  no  further  action,  such  as  the  Quassiins, 
Columbin,  and  a  few  weak  acids  and  glucosides. 


56  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

Pharmacological  Action. — These  substances,  or  rather  the  prepara- 
tions containing  them,  are  largely  used  in  therapeutics  in  order  to  in- 
crease the  appetite,  and  their  administration  is  often  followed  by  a  dis- 
tinct improvement  in  the  digestion  and  an  increase  in  weight. 

Alimentary  Tract. — The  explanation  of  these  effects  is  still  obscure, 
although  a  large  number  of  investigations  have  been  made  as  to  their 
effects  in  the  stomach.  In  experiments  with  artificial  digestion  the 
pure,  principles  have  generally  been  found  without  influence  on  the  ac- 
tivity of  both  gastric  and  pancreatic  fluids,  the  slight  variations  ob- 
served lying  within  the  limits  of  error ;  and  where  any  distinct  effect 
has  been  observed,  it  has  generally  been  a  retardation  of  the  process. 
The  ordinary  therapeutic  preparations,  on  the  other  hand,  generally 
delay  artificial  digestion,  owing  to  the  presence  of  tannic  acid  and  colloid 
substances.  The  bitters  neither  destroy  nor  greatly  retard  the  growth 
of  bacteria  in  culture  media,  and  most  of  them  seem  to  be  without  ef- 
fect on  the  yeast  fermentation  of  sugar  solutions,  although  Vas  found 
that  quassiin  retarded  it  somewhat.  The  absorption  from  the  stomach 
is  unchanged  by  the  presence  of  bitters. 

In  regard  to  the  effect  of  the  bitters  on  the  secretion  of  the  stomach, 
Reichmann  states  that  in  man  the  bitters  taken  during  gastric  digestion 
do  not  affect  the  secretion,  although  they  seem  to  retard  the  proteolysis. 
When  bitters  are  taken  on  .an  empty  stomach,  less  gastric  juice  is 
secreted  immediately  than  if  the  same  amount  of  water  had  been  swal- 
lowed, but  some  time  afterwards  a  very  active  secretion  occurs.  '/Reich- 
mann, therefore,  advises  the  bitters  in  cases  of  insufficient  acidity  of  the 
astric  juice,  the  remedy  to  be  taken  half  an  hour  before  meals.  yOn 
the  other  hand,  in  hyperacidity  the  bitters  may  aggravate  the  condi- 
tion. This  statement  is  in  accordance  with  the  observations  of  Bokai, 
that  the  secretory  cells  of  the  peptic  glands  present  the  histological 
)  appearances  of  activity  after  the  bitters  have  been  ingested. 

In  animal  experiments,  the  movements  of  the  stomach  are  said  to 

be  somewhat  augmented  by  the  bitters,  and  poisonous  doses  of  several 

of  them  increase  the  movements  of  both  stomach  and  bowel,  and  cause 

considerable  hypersemia.      But  it  is   unknown  whether  this  action   is 

QT/ common  to  all  the  bitters,  and  whether  the  small  quantities  used  in  ther- 

v  y    apeutics  cause  any  increase  in  the  blood  supply.     According  to  Reich- 

/     mann,  the  movements  are  probably  somewhat  less  than  usual  in  man. 

|      Pohl  found  that  bitters  given  by  the  stomach  increase  to  a  marked 

/extent  the  leucocytes  in  the  blood  of  the  dog,  and  Ramm  has  shown 

I  that  this  holds  true  for  man,  and  adds  that  the  red  blood-cells  are  also 

augmented.     The  secretions  of  the  pancreas  and  the  bile  are  unaffected 

Iby  the  bitters,  but  intestinal   secretion  and  absorption  are  increased  an 

f  hour  after  bitters  reach  the  intestine   (Jodlbauer).     In  the  mouth  the 

bitters  cause  a  reflex  flow  of  saliva,  and  it  has  been  suggested  that  this 

may  in  part  explain  their  therapeutic  effect.     Large  quantities  are  said 

to  cause  a  burning  sensation  in  the  oasophagus  and  stomach. 

The  whole  literature  on  the  action  of  the  bitters  is  full  of  contradic- 
tions, which  is  perhaps  to  be  explained  by  the  fact  that  comparatively 


SIMPLE  BITTERS.  57 

few  investigators  have  examined  their  effect  in  human  digestion,  and 
many  have  contented  themselves  with  the  results  of  intravenous  injec- 
tion in  animals.  The  most  probable  explanation  is  that  of  Reichmann, 
that  the  gastric  secretion  is  increased.  It  may  be  suggested  here  that 
this  does  not  involve  a  direct  action  on  the  secretory  epithelium,  for 
I  Pawlow  and  his  pupils  have  shown  that  the  chief  factor  that  deter - 
I  mines  the  activity  of  the  gastric  secretory  cells  is  the  odor  and  taste  of 
I  the  food.  In  dogs  with  gastric  fistulse,  in  which  the  food  swallowed 
did  not  pass  into  the  stomach  but  escaped  through  a  wound  in  the 
resophagus,  the  taste  and  odor  of  food  caused  a  profuse  reflex  secretion 
of  gastric  juice,  and  bitters  given  shortly  before  augmented  this  reflex 
(Borissow).  It  is  quite  possible  that  bitter  tastes  may  cause  this  reflex 
secretion  in  man,  and  that  the  whole  effect  may  be  explained  by  the 
one  property  common  to  all  these  drugs — their  bitter  taste.  In  addi- 
tion, it  is  to  be  remembered  that  the  improvement  is  largely  subjective, 
and  that  the  bitters  are  capable  of  producing  a  considerable  impression 
upon  patients,  so  that  the  effects  may  be  due  in  part  to  suggestion  and 
not  to  any  real  action  of  the  drug. 

Action  after  Absorption. — In  very  large  quantities  some  of  the  bitters 
produce  effects  that  are  obviously  due  to  their  absorption.  These  have 
seldom  been  observed  in  man,  but  have  been  studied  in  animal  experiments. 
Thus  Compardon  states  that  in  many  individuals  0.12  G.  of  quassiin  produces 
burning  in  the  throat  and  stomach,  discomfort,  headache,  nausea,  and 
vomiting.  In  flies  and  other  insects  it  has  a  narcotic  action.  Columbin  and 
cetrarin  were  found  by  Kohler  to  increase  the  blood  pressure  by  stimulation 
of  the  vasomotor  centre  when  they  were  injected  intravenously.  Ramm 
states  that  the  intravenous  injection  of  cetrarin  causes  irritation  of  the 
stomach  and  bowel,  purging  and  vomiting,  and  general  paralysis  of  the 
central  nervous  system,  which  is  preceded  by  convulsions  in  mammals.  He 
did  not  observe  any  increase  in  the  blood  pressure.  Both  the  glucosides  of 
condurango  produce  in  dogs  ataxia  and  loss  of  coordination,  with  increased 
movement,  and  eventually  convulsions,  and  death  follows  in  12-72  hours  or 
longer.  The  brain  seems  the  part  chiefly  affected  in  mammals,  although  the 
reflex  excitability  of  the  spinal  cord  is  also  augmented  in  the  frog  (Jukna). 
Buxine  possesses  considerable  antiseptic  power,  and  prevents  the  movement 
of  leucocytes  and  of  the  lower  organisms  in  the  same  way  as  quinine.  Large 
doses  often  cause  vomiting,  confusion,  giddiness  and  tremor,  with  diarrhoea 
in  dogs,  but  are  sometimes  without  effect.  Aristolochine,  which  has  been 
found  in  several  species  of  Aristolochia,  and  probably  occurs  in  the  official 
serpentary,  produces  in  rabbits  acute  necrotic  nephritis,  with  albuminuria 
and  ursemic  symptoms.  In  dogs  it  causes  a  very  marked  fall  of  blood  pres- 
sure, and  hemorrhages  in  the  intestinal  mucous  membrane,  but  no  nephritis. 
The  poisonous  action  of  aristolochine  is  very  similar  to,  but  much  more 
powerful  than  that  of  aloin  (Pohl).  Lupulinic  acid  obtained  from  hops, 
when  injected  as  a  neutral  salt  into  the  blood,  causes  first  stimulation  and 
then  paralysis  of  the  medullary  centres,  but  has  very  little  effect  when  given 
by  the  stomach  even  in  large  doses  (Dreser).  In  beer  an  oxidized  product 
of  lupulinic  acid  occurs,  which  has  no  effect  even  when  injected  into  the 
blood.  Berberlne  is  a  very  widely  distributed  alkaloid  of  the  pyridine  series 
(C20H17NO4),  and  when  administered  in  very  large  quantities  per  os,  causes 
diarrhoea,  and  occasionally  vomiting,  tremor,  acceleration  of  the  pulse  and 
respiration  and  general  weakness,  from  which  the  animal  recovers  only 
slowly.  Its  subcutaneous  or  intravenous  injection  is  followed  by  the  same 


58  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

symptoms,  but  paralysis  of  the  hind  extremities,  convulsions,  and  asphyxia 
from  failure  of  the  respiratory  centre  may  occur  when  it  is  administered  in 
this  way,  while  the  largest  quantities  are  not  fatal  when  exhibited  by  the 
stomach.  The  acceleration  of  the  pulse  seems  due  to  paralysis  of  the  inhibi- 
tory terminations  in  the  heart,  and  is  accompanied  by  a  fall  of  blood  pres- 
sure from  the  effects  of  the  alkaloid  on  the  vasomotor  centre  and  on  the 
heart  directly.  Berberine  has  been  credited  with  causing  contraction  of  the 
uterus  and  of  the  spleen,  but  this  is  disputed.  It  has  also  been  said  to 
resemble  quinine  in  its  effects  on  bacteria  and  on  the  leucocytes,  but  only  in 
very  strong  solution.  Berberine  seems  to  be  excreted  in  part  by  the  kidney 
unchanged,  and  is  said  to  cause  nephritis  in  large  doses. 

The  cotoin  of  Goto  bark,  and  the  paracotoin  and  other  constituents  of 
Paracoto  bark  are  said  to  cause  dilatation  of  the  intestinal  vessels  when  they 
are  injected  intravenously  or  perfused  through  the  mesenteric  vessels.  Para- 
cotoin is  much  weaker  than  cotoin. 

Orexine  (C14H12N2),  an  artificial  base,  seems  to  stand  midway  between  the 
peppers  and  the  bitters  in  its  action,  as  it  is  somewhat  more  irritating  than 
most  of  the  latter.  Injected  into  the  frog  it  induces  paralysis,  which  is  ap- 
parently of  peripheral  origin,  and  its  subcutaneous  application  in  mammals 
is  followed  by  tremor,  tonic  and  clonic  convulsions,  dyspnoea,  acceleration 
of  the  heart  and  vomiting.  It  has  some  antiseptic  action,  and  tends  to  form 
methsemoglobin  when  mixed  with  the  blood.  No  symptoms  have  been  ob- 
served from  its  use  in  man,  except  increased  appetite  and  augmentation  of 
the  gastric  secretion,  and  in  a  few  cases  a  feeling  of  heat  in  the  throat  and 
some  nausea. 

PREPARATIONS. 

Gentiana  (U.  S.  P.),  Gentianse  Radix  (B.  P.),  gentian,  the  root  of  Genti- 
ana  lutea,  contains  a  glucoside,  gentiopicrin,  a  neutral  body,  gentisin,  and 
a  trace  of  tannic  acid.  1  G.  (15  grs.). 

EXTRACTUM  GENTIANS  (U.  S.  P.,  B.  P.),  0.1-0.5  G.  (2-10  grs.). 

Fluidextractum  Gentiance  (U.  S.  P.),  0.5-2  c.c.  (10-30  mins.). 

TINCTURA  GENTIANS  COMPOSITA  (U.  S.  P.,  B.  P.),  containing  gentian, 
bitter  orange  peel,  and  cardamom,  2-16  c.c.  (|-4  fl.  drs.). 

Infusum  Gentians?  Compositum  (B.  P.),  containing  gentian,  bitter  orange 
peel,  and  fresh  lemon  peel,  \-\  fl.  oz. 

Quassia  (U.  S.  P.),  Quassiae  Lignum  (B.  P.),  the  wood  of  PicraBua  excelsa, 
contains  several  neutral  bitter  substances,  resembling  each  other  closely 
chemically  and  known  as  quassiins. 

EXTRACTUM  QUASSIA  (U.  S.  P.),  0.05-0.2  G.  (1-3  grs.). 

Fluidextractum  Quassice  (U.  S.  P.),  0.5-2  c.c.  (5-30  mins.). 

TINCTURA  QUASSIA  (U.  S.  P.,  B.  P.),  1-4  c.c.  (15-60  mins.). 

Liquor  Quassise.  Concentratus  (B.  P.),  |-1  fl.  dr. 

INFUSUM  QUASSIA  (B.  P.),  \-\  fl.  oz. 

Calumba  (U.  S.  P.),  Calumbse  Eadix  (B.  P.),  columbo,  the  root  of  Jateor- 
rhiza  palmata,  or  Columba,  contains  columbin,  a  neutral  body,  columbic  acid, 
and  the  alkaloid  berberine. 

Fluidextractum  Calumbce  (U.  S.  P.),  1-2  c.c.  (15-30  mins.). 

TINCTURA  CALUMBCE  (U.  S.  P.,  B.  P.),  4-15  c.c.  (1-4  fl.  drs.). 

Infusum  Calumbce  (B.  P.),  ^-1  fl.  oz. 

Liquor  Calumbce,  Concentratus  (B.  P.),  ^-1  fl.  dr. 

Chirata  (U.  S.  P.,  B.  P.),  Chiretta,  the  plant  Swertia  chirata,  contains  a 
glucoside,  chiratin,  and  ophelic  acid. 

Fluidextractum  Chiratw  (U.  S.  P.),  0.3-1  c.c.  (5-15  mins.). 

Tinctura  Chiratce  (B.  P.),  4-8  c.c.  (1-2  fl.  drs.). 

Liquor  Chiratce  Concentratus  (B.  P.),  £-1  fl.  dr. 

Infusum  Chiratce  (B.  P.),  \-\  fl.  oz. 

Taraxacum  (U.  S.  P.),  Taraxaci  Radix  (B.  P.),  the  root  of  the  dandelion, 


SIMPLE  BITTERS.  59 

Taraxacum  officinale,  contains   two   neutral   bitter   substances — taraxacin   and 
taraxacein. 

Extractum  Taraxaci  (U.  S.  P.,  B.  P.),  0.3-1  G.  (5-15  grs.).  • 

Fluidextractum  Taraxaci  (U.  S.  P.),  Extractum  Taraxaci  Liquidum  (B.  P.), 
4-12  c.c.  (1-3  fl.  drs.). 

Succus  Taraxaci  (B.  P.),  1-2  fl.  drs. 

Berberis  (U.  S.  P.),  barberry,  the  rhizome  and  roots  of  various  species  of 
Berberis,  contains  berberine  and  tannin,  2  G.  (30  grs.). 

Fluidextractum  Berberidis  (U.  S.  P.),  2  c.c.  (30  mins.). 

Pareira  (U.  S.  P.),  Pareirae  Radix  (B.  P.),  the  root  of  Chondrodehdron 
tomentosum,  contains  an  alkaloid,  buxine. 

Fluidextractum  Pareifce  (U.  S.  P.),  Extractum  Pareivce  Liquidum  (B.  P.), 
2-8  c.c.  Q-2  fl.  drs.). 

Serpentaria  (U.  S.  P.),  Serpentariae  Rhizoma  (B.  P.),  snake-root,  the  rhi- 
zome and  roots  of  Aristolochia  serpentaria  and  of  Aristolochia  recticulata, 
contains  a  volatile  oil,  an  unknown  bitter  principle,  and  perhaps  an  alkaloid, 
aristolochine. 

Fluidextractum  Serpentarice  (U.  S.  P.),  1-2  c.c. 

Tinctura  Serpentaria  (U.  S.  P.,  B.  P.),  2-8  c.c.  (£-1  fl.  dr.). 

Liquor  /Serpentarice  Concentratus  (B.  P.),  5— 2  fl.  drs. 

Infusum  /Serpentarice  (B.  P.),  ^-1  fl.  oz. 

Hunmlus  (U.  S.  P.),  Lu.pu.lus  (B.  P.),  hops,  the  strobiles  of  Humulus  lupu- 
lus,  and  Lupulin,  a  glandular  powder  separated  from  hops,  contain  a  volatile 
oil,  a  bitter  neutral  substance,  lupulin,  lupulinic  acid,  and  resins. 

Fluidextractum  Lupulini  (U.  S.  P.),   2-8  c.c.  (£-2  fl.  drs.). 

Oleoresina  Lupulini  (U.  S.  P.),  0.1-0.3  G.  (2-5  grs.). 

Lupulinum  (B.  P.),  2-5  grs. 

Infusum  Lupuli  (B.  P.),  1-2  fl.  oz. 

Tinctura  Lupuli  (B.  P.),  i-1  fl.  dr. 

Cuspariae  Cortex  (B.  P.),  Angostura  bark,  the  dried  bark  of  Cusparia  feb- 
rifuga,  contains  four  or  more  alkaloids,  cusparine,  cusparidine,  galipine,  and 
galipidine,  along  with  a  volatile  oil  and  a  neutral  bitter  stuff. 

Infusum  Cusparise  (B.  P.),  1-2  fl.  oz. 

Liquor  Cusparise.  Concentratus  (B.  P.),  £-1  fl.  dr. 

Nectandrae  Cortex,  Bebeeru  bark,  is  not  pharmacopoeial,  but  is  occasion- 
ally used  in  therapeutics.  It  contains  an  alkaloid  which  is  now  known  to  be 
buxine,  but  which  has  been  called  beberine,  biberine,  or  bebeerine  hitherto. 
Buxine  or  beberine  sulphate  is  prepared  from  it. 

Condurango,  the  bark  of  Goiiolobus  condurango,  contains  two  glucosides 
of  similar  properties,  and  has  been  used  a  good  deal  of  late  years  as  a  stom- 
achic bitter.  It  was  formerly  credited  with  a  specific  action  on  epithelioma. 

Cetraric  acid,  or  cetrarin,  is  obtained  from  Iceland  moss  (see  page  47),  and 
has  been  recommended  as  a  bitter  in  doses  of  about  0.1  G.  (2  grs.),  in  tablets. 

Coto  bark,  whose  origin  is  still  doubtful,  contains  cotoin  (C^HisOe),  aiul 
has  been  used  to  form  a  fluid  extract.  Dose,  0.3-1.5  c.c.  (5-20  mins.). 
Cotoin  has  been  prescribed  in  the  dose  of  0.03-0.2  G.  (£-3  grs.). 

Orexine  Hydrochlorate,  C6H4NoC2H3C6H5HCl,  is  a  colorless,  crystalline 
body,  soluble  in  about  15  parts  of  water,  with  a  bitter,  somewhat  pungent 
taste.  It  is  prescribed  in  powder  or  tablets.  Dose,  0.3  G.  (5  grs.). 

Bael  fruit,  or  Bengal  quince,  was  formerly  contained  in  the  B.  P.,  but  has 
been  omitted  in  the  last  edition.  Very  little  is  known  regarding  its  action 
or  principles,  but  it  may  perhaps  have  some  effect  as  a  bitter. 

Many  other  bitter  stomachics  might  be  enumerated,  some  of  which 
have  been  used  largely  in  former  times,  but  as  they  are  all  identical  in 
their  effects,  it  seems  unnecessary  to  do  so. 

Instead  of  the  simple  bitters,  cinchona  and  mix  vomica  preparations 
are  often  used  in  small  quantities.  Many  of  the  preparations  which 


60  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

will  be  enumerated  under  the  volatile  oil  series  owe  much  of  their 
effect  to  the  bitter  which  accompanies  the  volatile  oil,  and  in  numerous 
other  pharmacopreial  preparations  bitters  are  present,  although  their 
eifect  is  hidden  by  the  action  of  the  drug  in  other  directions. 

Therapeutic  Uses. — The  bitters  are  used  chiefly  to  increase  the  appe- 
tite and  the  digestion.  In  convalescents,  in  persons  of  sedentary 
habits,  and  occasionally  in  chronic  dyspeptic  conditions  they  are  of 
value,  while  in  cases  of  more  acute  gastric  irritability  they  may  do 
harm  rather  than  good.  Gentian,  Quassia,  Calumba  and  Chirata  are 
the  only  simple  bitters  that  are  largely  used,  and  the  first  is  much  the 
most  important.  They  are  generally  prescribed  as  tinctures,  fluid  ex- 
tracts or  other  fluid  preparations.  The  last  three  may  be  prescribed 
with  iron  preparations,  as  they  contain  little  or  no  tannic  acid  and 
thus  cause  no  precipitate.  Pills  are  sometimes  prescribed  with  extract 
of  gentian  or  quassia,  but  it  seems  open  to  question  whether  these  in- 
gredients have  really  any  eifect  when  given  in  this  form.  Compound 
tincture  of  gentian  is  sometimes  used  to  give  flavor  rather  than  for  any 
effect  on  the  digestion. 

Quassia  infusion  (ten  per  cent.)  is  injected  as  an  enema  in  the  round 
worms  of  children. 

Several  of  the  drugs  mentioned,  such  as  taraxacum  and  gentian,  have  been 
supposed  to  have  a  specific  action  on  the  liver,  but  there  are  no  sufficient 
grounds  for  this  belief.  The  supposed  virtues  of  pareira  as  a  diuretic  and 
of  berberine,  buxine,  and  other  alkaloids  as  substitutes  for  quinine  in  ma- 
laria have  also  proved  to  have  no  foundation,  and  the  popular  reputation  of 
hops  as  a  narcotic  probably  arises  from  its  association  with  alcohol  in  beer. 
Cotoin  and  Goto  bark  are  said  to  have  some  special  effect  in  lessening  diar- 
rhoea, in  addition  to  their  action  as  bitters. 

BIBLIOGRAPHY. 

Bokai,  Reusz,   Vas,  Huber  and  Gara.     Ungar.  Arch,  fur  Medicin,  ii.,  pp.  295-325. 

Gottlieb.     Arch.  f.  exp.  Path.,  xxxiii.,  p.  261. 

Brandl     Zts.  f.  BioL,  xxix.,  p.  277. 

Scanzoni.     Ibid.,  xxxiii.,  p.  462. 

Jodlbauer.     Arch,  internal,  d.  Pharmacodyn.,  x.,  p.  201. 

Pawlow  and  Schumowa-Simanowskaja.     Arch.  f.  [Anat.  u.]  Phys.,  1895,  p.  53. 

Binz.     Virchow's  Arch.,  xlvi.,  p.  129. 

Jukna.     Arb.  des  pharmak.  Instit.  Dorpat,  iv.,  p.  81.     (Coridurango.) 

Pohl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix.,  p.  282.     (Aristolochine.) 

Farkas.     Pfliiger's  Archiv,  xcii.,  p.  61.     (Lupulinic  acid.) 

K.  v.  Bunye.    'Arb.  des  pharmak.  Institut.  Dorpat,  xi.-xii.,  p.  135.     (Berberine.) 

Mosse  u.  Tautz.     Ztschr.  f.  klin.  Med.,  xliii.,  p.  257. 

Ramm.     Historische  Studien  a.  d.  pharmak.  Instit.  Dorpat,  ii.,  p.  1 . 

Borissow.     Arch.  f.  exp.  Path.  u.  Pharm.  Ii.,  p.  363. 

Karb.     Deut.  Arch.  f.  klin.  Med.,  Ixxvi.,  p.  30.     (Goto.) 

Reichmann.     Ztschr.  f.  klin.  Med.,  xiv.,  p.  177. 

Kobert.     International  Congress  Berlin,  1890,  iv.,  p.  58.      (Cetrarin.) 

Penzoldt.     Therap.  Monatsh.,  1890,  p.  59.     (Orexine. ) 

Kronfeld.     Wiener  klin..  Woch.f  1891,  p.  45.     (Orexine. ) 


VOLATILE  OIL  SERIES.  61 

V.     VOLATILE   OIL   SERIES. 

The  group  of  volatile,  ethereal,  or  essential  oils  contains  a  large 
number  of  preparations  in  the  pharmacopoeias  of  all  countries.  These 
oils  are  obtained  from  plants  by  distillation,  or  more  rarely  by  pres- 
sure, and  must  be  distinguished  by  the  student  from  the  fatty  or  fixed 
oils,  which  are  non-volatile.  The  volatile  or  ethereal  oils  are  found 
chiefly  in  the  fruits  and  flowering  parts  of  plants,  and  are  very  widely 
diffused  through  the  vegetable  kingdom,  though  some  orders,  such  as 
the  Labiatse,  Umbelliferse,  Aurantiacese,  Cruciferse,  and  Conifers  are 
preeminent  in  their  production.  They  are  all  strongly  odorous,  and 
are  therefore  used  in  perfumery,  and  to  conceal  nauseous  odors  and 
tastes  in  medicine. 

Their  composition  is  extremely  variable.  The  commonest  constituents  are 
Terpenes,  and  some  oils  contain  these  only,  while  in  a  few  oils  no  terpene  has 
been  found  (Attar  of  Roses).  Terpenes  are  hydrocarbons  of  the  aromatic  series, 
and  possess  the  general  formula  (C5H8)n.  The  great  majority  of  them,  or  the 
terpenes  proper  (C10H16),  are  combinations  of  a  dihydrobenzol  with  propyl  and 
methyl  (C6H4(H2)C3H7CH3).  Some  twelve  terpenes  of  this  formula  are  known, 
varying  in  their  chemical  structure  and  in  their  stereometrical  form.  Another 
group  of  these  hydrocarbons  is  formed  by  the  Sesquiterpenes  (C15H2J,  while  a  few 
Diterpenes  (C20H32)  are  known.  Some  volatile  oils  consist  of  these  hydrocarbons 
only,  but  many  of  them  contain  in  addition  some  oxidized  aromatic  substances, 
such  as  phenols,  ketones,  aldehydes,  acids  and  their  compounds  ;  as  instances 
of  these  may  be  cited  camphor,  thujon  (from  oil  of  absinth),  sabinol  (oil  of 
savine),  safrol,  thymol,  eucalyptol,  myristicol,  and  vanillin.  Many  of  these 
oxidized  products  crystallize  out  when  the  volatile  oil  is  cooled  sufficiently,  and 
especially  on  long  standing,  and  the  resulting  solid  is  known  as  a  Stearoptene, 
while  the  fluid  remaining  is  sometimes  called  Elceoptene.  The  oils  containing 
oxygen  are  not  so  volatile  as  the  pure  hydrocarbons,  but  the  odor  is  often  due 
chiefly  to  the  oxidized  substances.  A  very  few  oils  contain  nitrogenous  bodies, 
generally  in  the  form  of  cyanides,  while,  on  the  other  hand,  the  majority  of  the 
volatile  oils  of  the  Cruciferse  contain  sulphur  bodies,  which  lend  them  a  pungent, 
disagreeable  odor,  quite  different  from  that  of  the  other  oils. 

The  volatile  oils  are  generally  clear,  colorless  fluids,  although  some 
of  them  are  green  from  the  presence  of  small  quantities  of  vegetable 
coloring  matter,  while  others  are  blue  in  color  from  the  presence  of  a 
terpene  derivative  (azulene).  After  long  keeping  they  often  acquire 
a  yellowish  color  and  an  acid  reaction,  from  the  formation  of  resins. 
They  are  generally  light,  sparkling  fluids,  but  the  oils  of  copaiva  and 
cubebs  are  more  viscid.  They  are  insoluble  in  water  except  in  very 
small  amount,  which,  however,  is  enough  to  lend  their  characteristic 
odor  to  the  solution  ;  in  strong  alcohol,  ether,  benzol,  chloroform,  and 
fixed  oils,  they  are  freely  soluble. 

Many  of  the  plants  from  which  the  volatile  oils  are  obtained  possess 
other  active  constituents,  such  as  bitters,  and  as  many  of  the  prepara- 
tions used  in  therapeutics  are  formed,  not  from  the  distilled  oils,  but 
from  the  crude  parts  of  plants,  it  must  be  noted  that  the  oil  is  not  the 
only  active  principle  in  them.  A  series  containing  members  which 
differ  so  widely  chemically,  and  which  in  fact  have  only  their  volatility 
and  their  aromatic  nucleus  in  common,  could  not  be  expected  to  have 


62  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

a  uniform  action  in  the  animal  organism.  It  is  found,  however,  that 
they  resemble  each  other  in  their  therapeutic  properties,  because  they 
are  used  almost  solely  for  their  local  action,  and  that  in  only  small 
quantities.  Some  of  the  volatile  oil  preparations  which  are  employed 
for  their  general  effects,  will  be  discussed  later.  (See  Camphor.) 

Action  Externally. — The  volatile  oils  all  possess  antiseptic  properties, 
which  are  doubtless  due  in  part  to  their  volatility  enabling  them  to 
penetrate  readily  into  protoplasm  and  to  lessen  its  vitality  by  acting 
as  foreign  bodies.  In  addition,  they  are  nearly  related  to  the  benzol 
series,  the  members  of  which  are  all  antiseptics  and  protoplasm  poisons. 
They  differ  a  good  deal  in  their  germicidal  power,  and  are  much  more 
poisonous  to  the  moulds  than  to  the  bacteria.  The  most  active  oils 
are  those  containing  a  large  amount  of  terpene,  such  as  the  oil  of  tur- 
pentine. 

Their  volatility  may  also  explain  their  irritant  action  in  part,  for 
most  other  volatile  substances  are  more  or  less  irritant,  but  here  again 
their  relation  to  the  phenols  and  benzol  cannot  be  ignored.  Applied 
to  the  skin,  they  cause  redness,  itching  and  warmth,  owing  to  a  local 
dilation  of  the  vessels,  which  may  be  due  to  the  penetration  of  the  oil 
to  the  cutaneous  arterioles  or  veins,  or  to  a  reflex  from  the  irritated 
terminations  of  the  sensory  nerves  acting  on  the  vasomotor  centres. 

When  painted  on  the  mucous  membranes,  such  as  those  of  the  eye 
or  nose,  or  on  wounds,  the  volatile  oils  cause  similar  irritation,  which 
is  betrayed  by  redness  and  congestion,  pain  and  smarting. 

Action  on  the  Alimentary  Canal. — Strong  solutions  of  the  oils  act 
as  irritants  in  the  mouth.  They  have  generally  a  hot,  burning  taste, 
and  if  kept  in  the  mouth,  cause  redness  and  irritation  of  the  mucous 
membranes,  although  some  of  them  induce  a  sense  of  coolness  at  first. 
At  the  same  time  the  organs  of  smell  are  affected  by  these  oils,  which 
are  almost  all  possessed  of  characteristic  odors.  The  irritation  of  the 
mouth  leads  to  a  reflex  secretion  of  saliva,  which  is  often  very  profuse. 
The  antiseptic  action  of  the  oils  is  exercised  in  the  mouth  as  elsewhere, 
and  may  have  a  beneficial  effect  in  some  conditions. 

On  passing  into  the  stomach,  the  oils  cause  the  same  sensation  of 
warmth  in  that  organ,  and  this  is  accompanied  by  a  sense  of  well- 
being  and  comfort,  the  appetite  is  often  increased,  and  any  feeling  of 
distention  after  meals  is  relieved.  This  is  often  attended  by  the  eruc- 
tation of  quantities  of  gas.  Substances  which  produce  these  effects  in 
the  stomach  are  known  as  carminatives,  and  many  explanations  of  their 
action  have  been  offered.  The  oils  undoubtedly  act  as  antiseptics  here 
as  elsewhere,  and  may  hinder  the  development  of  yeasts  and  other 
organisms  and  thus  be  of  benefit,  but  this  would  not  give  the  imme- 
diate feeling  of  relief  which  is  often  experienced  after  a  small  quantity 
of  these  remedies.  The  process  of  digestion  seems  to  be  rather  re- 
tarded than  accelerated  by  the  presence  of  the  oils,  as  far  as  can  be 
.adged  by  test-tube  experiments  and  by  some  measurements  made  by 
Suchheim  on  the  digestion  of  animals  with  gastric  fistulse.  The  secre- 
tion of  the  gastric  glands  has  been  said  to  be  increased  by  the  direct 


VOLATILE  OIL  SERIES.  63 

action  of  the  volatile  oils,  but  this  has  been  disputed.  But  it  must 
not  be  forgotten  that  the  most  powerful  stimulant  to  gastric  secretion 
is  the  smell  and  taste  of  food,  and  that  substances  of  agreeable  taste 
and  odor  cause  a  marked  increase  in  the  gastric  juice  by  reflexes  from 
the  mouth  and  nose.  An  argument  for  the  direct  action  of  the  volatile 
oils  on  the  secretory  glands  has  been  drawn  from  the  observation  that, 
applied  to  the  frog's  skin,  they  induce  a  profuse  local  secretion,  but  this 
is  scarcely  sufficient  basis  for  an  explanation.  The  eructation  of  gas 
certainly  suggests  that  the  volatile  oils  accelerate  the  movements  of  the 
stomach,  and  this  has  been  repeatedly  confirmed  by  the  direct  observa- 
tion of  the  stomach  walls.  Brandl  has  also  shown  recently  that  absorp- 
tion occurs  much  more  rapidly  from  the  stomach  in  the  presence  of 
slight  irritants,  such  as  the  volatile  oils.  Finally  it  must  be  added  that 
many  of  the  beneficial  effects  are  purely  subjective  ;  the  patient  has  a 
feeling  of  warmth  and  comfort  in  the  region  of  the  stomach,  arising 
from  the  slight  irritation  and  consequent  hyperaBmia  of  the  mucous 
membrane,  but  this  does  not  necessarily  indicate  any  marked  altera- 
tion in  the  processes  of  digestion  or  in  the  movements  of  the  stomach. 

Similar  effects  are  believed  to  be  produced  in  the  intestine,  for  the 
administration  of  these  oils  is  often  followed  by  an  improvement  in  its 
condition,  manifested  by  lessened  flatulence  and  distention,  and  relief  is 
given  by  their  use  in  some  forms  of  colic.  The  antiseptic  action  may 
play  a  part  in  these  effects.  Scanzoni  and  Farnsteiner  have  recently 
shown  that  the  intestine,  like  the  stomach,  absorbs  more  rapidly  in  the 
presence  of  small  quantities  of  the  oils.  The  pancreatic  secretion  was 
supposed  to  be  increased  by  their  irritant  action  in  the  stomach,  through 
a  reflex  travelling  both  centripetally  and  centrifugally  along  the  vagus 
fibres  (Gottlieb),  but  Schirokikh  asserts  that  this  is  true  only  when 
large  quantities  produce  very  marked  gastric  irritation.  Whether  the 
peristaltic  movements  of  the  bowel  are  increased  by  the  volatile  oils 
is  quite  unknown.  It  is  believed,  however,  that  their  administration 
lessens  the  pain  and  griping  produced  by  some  of  the  more  powerful 
purgatives,  and  several  pharmacopoeial  preparations  are  formed  on  this 
theory,  which  is  supported  by  many  years  of  clinical  experience. 

A  considerable  increase  in  the  leucocytes  of  the  blood  follows  their 
ingestion  by  the  mouth,  but  this  is  observed  in  congestion  of  the 
stomach  and  intestine  from  other  causes  and  is  not  induced  by  the  sub- 
cutaneous or  intravenous  injection  of  the  volatile  oils,  so  that  it  cannot 
be  regarded  as  a  specific  effect.  Winternitz  found  that  irritation  of 
the  pleura  causes  less  purulent  exudate  in  animals  treated  with  some 
volatile  oils  than  in  controls  which  were  not  treated  in  any  way,  and 
concludes  that  the  presence  of  the  oils  in  the  blood  lessens  the  exudate 
and  also  promotes  its  absorption ;  he  is  inclined  to  regard  this  anti- 
phlogistic action  as  a  result  of  the  leucocy  tosis  and  of  a  supposed  attrac- 
tion exercised  on  the  leucocytes  by  the  oils,  which  prevents  their  wander- 
ing into  the  tissues. 

Excretion.  —  Like  other  bodies  of  the  aromatic  series,  they  tend  to 
undergo  a  partial  oxidation  in  the  body ;  thus  the  terpenes  (C10H16) 


64  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

become  terpenols  (C^H^OH),  and  several  derivatives  of  the  terpenes 
have  been  shown  to  undergo  a  similar  change  of  a  hydrogen  atom  to 
hydroxyl,  while  others  which  contain  the  -OH  group  originally,  remain 
unaltered.  The  odor  of  the  original  oil  or  of  these  derivatives  may  often 
be  detected  in  the  breath,  showing  that  a  small  part  is  excreted  by  the 
lungs,  and  possibly  traces  may  be  eliminated  by  the  skin.  Some  also 
escapes  by  the  kidney  uncombined  and  imparts  an  odor  to  the  urine 
either  of  the  original  oil  or  of  some  oxygen  derivative ;  for  instance, 
oil  of  eucalyptus  or  of  turpentine  gives  the  urine  a  violet  odor.  But 
much  of  the  hydroxyl  product  is  combined  with  glycuronic  acid  and 
escapes  in  the  urine  in  this  form,  while  some  may  combine  to  form 
conjugate  sulphates.  The  glycuronic  acid  reduces  Fehling's  solution, 
especially  when  the  urine  is  previously  boiled  with  acid,  so  that  the 
volatile  oils  were  formerly  credited  with  inducing  glycosuria.  Some 
of  the  constituents  of  the  oils  are  oxidized  to  acids  and  excreted  in  the 
urine  as  salts. 

In  the  course  of  excretion,  some  of  the  oils  cause  irritation  of  the 
lungs  and  kidneys,  so  that  some  of  them  are  employed  to  increase  the 
bronchial  secretion,  while  others  have  a  distinct  diuretic  action.  This 
irritant  action  is-  of  course  not  confined  to  the  tissue,  but  extends  to 
microbial  guests,  so  that  the  volatile  oils  have  been  given  internally 
with  the  intention  of  destroying  or  retarding  the  growth  of  bacteria  in 
the  lungs,  and  some  of  them  are  used  almost  exclusively  for  their  anti- 
septic action  in  the  urine. 

Poisoning.  —  The  various  oils  differ  a  good  deal  in  their  activity, 
while  resembling  each  other  closely  in  the  general  characters  of  their 
effects.  All  of  them  may  produce  marked  irritation  of  the  stomach 
and  bowel  when  given  in  large  quantities,  but  the  oils  of  tansy,  sage, 
and  English  pennyroyal  are  distinguished  especially  by  the  violent  in- 
flammation they  cause,  and  by  the  frequency  with  which  fatal  poison- 
ing occurs  from  their  use.  The  terpenes  appear  to  be  but  slightly 
poisonous,  and  their  effects  are  probably  limited  to  local  irritation ;  the 
oxidized  aromatic  substances  have  been  shown  to  be  the  poisonous  con- 
stituents in  all  the  oils  hitherto  examined.  The  symptoms  are  those 
of  acute  gastric,  intestinal,  and  often  renal  irritation — vomiting,  purg- 
ing, acute  pain  in  the  abdomen,  blood  in  the  stools  and  in  the  vomited 
matter,  collapse,  weakness  of  the  pulse  and  respiration,  anuria,  or 
albumin  and  blood  in  the  urine,  and  convulsive  attacks  ending  in  coma 
and  death.  Great  hypersemia  of  the  abdominal  organs,  often  blood  in 
the  peritoneal  cavity,  and  sometimes  acute  inflammation  of  the  kidney 
are  the  chief  post-mortem  appearances.  The  hypersemia  and  conges- 
tion of  the  organs  of  the  abdomen  may  cause  abortion  in  pregnancy,  or 
increase  the  menses,  and  in  the  majority  of  cases  of  poisoning,  these 
oils  have  been  taken  with  the  object  of  inducing  abortion.  In  many 
instances,  however,  the  drug  has  proved  fatal  without  this  end  being 
achieved. 


VOLATILE  OIL  SERIES.  65 

General  Action. — The  small  quantities  of  volatile  oils  administered  in  or- 
dinary medicinal  use  pass  through  the  tissues  without  modifying  them  per- 
ceptibly, their  only  effects  arising  in  the  organs  by  which  they  are  absorbed 
and  excreted.  In  large  quantities,  however,  some  of  them  (the  oils  of  worm- 
wood, nutmeg,  sage,  savine  among  others)  produce  symptoms  which  indi- 
cate an  affection  of  the  central  nervous  system  quite  apart  from  their  local 
action.  The  latter  also  produces  nervous  effects  reflexly,  and  it  has  been 
found  exceedingly  difficult  to  distinguish  these  indirect  results  from  those 
caused  by  the  direct  action  on  the  central  nervous  system.  A  good  deal  of 
divergence  is  to  be  found  in  the  statements  of  different  writers  from  this  cause, 
and  also  from  the  fact  that  comparatively  few  researches  have  been  carried 
out  with  pure  principles.  Many  of  the  oils  vary  in  their  constituents  accord- 
ing to  the  climate,  the  season  of  the  year,  and  other  conditions  under  which 
the  plant  was  grown,  and  some  of  the  confusion  may  arise  from  differences 
in  the  oils  used  by  investigators.  Almost  all  the  oils  hitherto  examined  cause 
depression  and  final  paralysis  in  the  frog.  The  action  seems  to  be  mainly  on 
the  brain,  larger  quantities  being  required  to  paralyze  the  spinal  cord  than  to 
prevent  all  spontaneous  movements.  This  stage  of  depression  is  preceded 
by  one  of  excitement  after  oil  of  wormwood  and  some  others.  Some  of  the 
oils  paralyze  the  terminations  of  the  motor  nerves  in  voluntary  muscle  like 
curara  and  camphor. 

In  mammals  the  general  action  of  the  constituents  of  the  volatile  oils  seems 
to  involve  a  preliminary  stimulation  and  subsequent  depression  of  the  nerve 
cells.  The  relative  importance  of  these  two  stages  differs  in  different  oils, 
some,  e.  </.,  turpentine  oil,  causing  only  a  transient  excitement,  followed  by 
marked  weakness  and  depression,  while  others,  such  as  the  oil  of  absinth, 
cause  very  marked  excitement  and  convulsions.  The  activity  of  the  oils 
as  nervous  poisons  also  varies  greatly,  some  producing  only  insignificant 
effects  on  the  central  nervous  system  compared  with  those  from  their  local 
action,  while  in  others,  such  as  the  oil  of  absinth  or  wormwood,  the  symp- 
toms from  the  nervous  system  predominate  in  cases  of  poisoning.  As  a 
general  rule  the  higher  divisions  of  the  central  axis  are  affected  more  than 
the  lower  and  epileptiform  or  clonic  convulsions  may  be  induced  (camphor),  or 
tremors  similar  to  those  described  under  carbolic  acid  and  presumably  of  similar 
origin  (safrol  and  nutmeg  oil).  In  many  cases  a  combination  of  excitement  and 
ataxia  is  observed,  the  animal  moving  about  restlessly,  but  being  unable  to 
balance  itself.  In  the  later  stages  of  poisoning  the  spontaneous  movements 
cease,  while  the  excitation  of  the  lower  centres  still  persists,  and  wild  convul- 
sive movements  accompany  the  final  arrest  of  the  respiration. 

The  medullary  centres  are  also  affected  differently  by  the  various  oils  and 
their  constituents.  The  respiration  is  finally  depressed  by  all  of  them,  but 
this  depression  is  often  preceded  by  stimulation,  the  breathing  increasing 
both  in  rapidity  and  in  volume.  The  vasomotor  centre  undergoes  similar 
changes,  the  blood-pressure  falling  from  some  oils  immediately,  from  others 
only  after  a  preliminary  increase. 

The  heart  does  not  seem  to  be  affected  by  most  of  the  volatile  oils,  except 
indirectly.  In  cases  of  poisoning  the  collapse  and  shock  may  alter  the 
character  of  its  contractions,  but  direct  effects  on  the  cardiac  muscle  have 
not  been  shown  to  be  produced  by  the  volatile  oils,  unless  when  enormous 
quantities  are  injected  intravenously. 

Heffter  and  Lindemann  have  recently  shown  that  some  of  the  constituents 
of  the  oils  cause  fatty  degeneration  of  various  organs,  especially  of  the  liver 
and  kidney,  while  others  of  very  similar  constitution  have  no  such  effect. 

Large  quantities  of  the  volatile  oils  often  produce  a  considerable  fall  in  the 
temperature. 

Although  these  general  effects  of  the  volatile  oils  have  no  therapeutic  im- 
portance, the  frequent  occurrence  of  epilepsy  and  insanity  in  habitual  ab- 
sinth drinkers  have  given  them  some  practical  interest, 
5 


66  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

Different  oils  are  used  for  different  purposes  in  therapeutics,  although 
they  all  resemble  each  other  in  most  respects,  and  it  is,  therefore,  con- 
venient to  divide  them  into  several  therapeutic  classes.1  A  number 
of  the  less  irritant  members  are  used  very  largely  as  flavoring  agents, 
for  their  carminative  effects  on  the  stomach  and  intestine,  more  rarely 
as  antiseptics,  and  as  expectorants.  Another  small  class  may  be  formed 
of  the  malodorous  oils,  a  third  of  those  used  as  gen i to-urinary  disin- 
fectants, while  several  which  contain  a  large  proportion  of  terpenes  and 
are  too  irritant  to  be  employed  as  carminatives,  will  be  discussed  among 
the  skin  irritants. 


1.  Volatile  Oils  Used  as  Flavoring  Agents  and  Carminatives. 

As  regards  their  use  as  flavoring  agents  but  little  need  be  said,  one 
preparation  is  used  by  one  physician,  another  by  another,  and  the  se- 
lection is  largely  a  matter  of  custom  and  taste.  The  orange  prepara- 
tions are  probably  more  generally  appreciated  by  patients  than  any 
others.  Carminatives  are  used  only  when  no  marked  irritation  of  the 
stomach  or  intestine  is  present,  in  cases  where  the  gastric  juice  seems 
unable  to  cope  with  the  food  ingested,  especially  in  persons  of  sedentary 
habits.  In  cases  of  colic,  flatulence  and  abdominal  distention  they  are 
often  of  use,  provided  that  these  are  not  due  to  peritonitis  and  other 
inflammatory  diseases.  Several  of  them  have  been  employed  as  sur- 
gical antiseptics,  notably  thymol,  but  its  insolubility  in  water  has  pre- 
vented its  extensive  adoption ;  they  are  more  widely  used  as  parasiti- 
cides for  scabies,  pediculi,  etc.  Some  of  the  oils,  such  as  oil  of  cloves, 
are  used  in  dentistry  to  relieve  pain,  and  also  for  their  antiseptic  action  ; 
the  relief  of  pain  is  due  to  their  paralyzing  the  exposed  nerve  ends 
after  a  preliminary  irritation.  Eucalyptus  has  been  advised  in  septic 
conditions  and  in  malaria,  and  at  one  time  was  supposed  to  be  a  spe- 
cific for  the  latter ;  it  improves  some  cases,  but  is  not  reliable,  and 
has  probably  no  more  effect  than  others  of  the  series.  Its  use  as  an 
internal  remedy  in  septicaemia  is  apparently  no  more  successful,  al- 
though it  still  enjoys  some  reputation  in  these  cases.  Volatile  oil 
preparations  are  sometimes  given  internally  in  the  hope  that  in  their 
excretion  through  the  lungs  they  will  exercise  an  antiseptic  action  in 
pulmonary  disease,  but  the  traces  excreted  in  this  way  are  quite  incap- 
able of  any  noticeable  effect  on  microbial  growth  and  the  tubercle  bacil- 
lus, against  which  these  measures  are  most  frequently  directed,  appears 
to  be  peculiarly  resistant  to  the  action  of  this  group  of  remedies. 
They  are  frequently  inhaled  with  a  similar  object.  Some  of  them  have 
been  used  as  anthelmintics  to  destroy  tapeworm  in  the  intestine,  and 
thymol  has  recently  proved  very  effective  in  destroying  the  intestinal 
parasites  in  uncinariasis  (see  Thymol).  Externally  some  of  them  are 
used  as  mild  skin-irritants,  generally  in  the  form  of  spirits.  Arnica 
has  a  great  popular  reputation  as  a  stimulating  local  remedy  in  bruises 

*Two  small  and  unimportant  groups  of  bodies  which  are  used  for  the  same  purposes 
as  some  of  the  volatile  oils  have  been  inserted  along  with  these. 


VOLATILE  OIL  SERIES.  67 

and  sprains,  although  it  has  no  specific  action  and  is  in  no  way  prefer- 
able to  the  other  members  of  the  series. 

The  volatile  oils  are  important  constituents  of  many  of  the  popular 
liqueurs,  such  as  Kummel,  Maraschino,  Curayoa,  Chartreuse,  etc.,  and 
therefore  have  a  certain  dietetic  importance. 

PREPARATIONS. 

Crude  Drugs. — Many  of  the  pharmacopoeial  preparations  are  whole  plants, 
seeds,  leaves  or  flowers,  and  are  never  prescribed,  although  some  of  them 
are  used  in  popular  medicine  in  the  form  of  infusions  or  "  teas."  The  virtues 
of  these  old-fashioned  remedies  lie  perhaps  more  in  the  large  draughts  of 
warm  water  than  in  the  traces  of  volatile  oil  which  they  contain,  but  the 
presence  of  the  latter  prevent,  to  some  extent,  the  nausea  produced  by  warm 
water  alone.  These  infusions  are  used  to  induce  perspiration  in  fevers  or 
chills,  as  diuretics,  or  to  relieve  colic  and  griping,  and  generally  contain 
about  a  tablespoonful  of  the  herb  to  one  or  two  cupfuls  of  water.  Those 
most  frequently  used  for  this  purpose  are  peppermint  and  spearmint  leaves 
and  tops  (Mentha  Piperita  and  Mentha  Viridis,  U.  S.  P.);  Coriander  seeds 
(Coriandrum,  U.  S  P.,  Coriandri  Fructus,  B.  P.)  ;  Chamomile  flowers  (Anthe- 
mis,  U.  S.  P.,  Anthemidis  Flores,  B.  P.,  and  Matricaria,  U.  S.  P.);  Anise 
(Anisum,  U.  S.  P.,  Anisi  Fructus,  B.  P.,  the  fruit  of  Pirnpinella  anisum); 
Elderflower  (Sambuci  Flores,  B.  P.);  and  Horehound  (Marrubium,  U.  S.  P., 
leaves  and  tops).  In  different  countries,  however,  the  constituents  of  the 
herbalist  recipes  vary  according  to  the  local  flora.  The  U.  S.  Pharmacopoeia 
recognizes  a  number  of  other  crude  drugs  of  this  group,  but  as  these  are  seldom 
or  never  prescribed,  they  need  only  be  enumerated  here:  Rosa  Gallica  (red  rose 
petals),  Eucalyptus,  Limonis  Cortex  (lemon  peel),  Aurantii  Dulcis  Cortex,  Auran- 
tii  Amari  Cortex  (sweet  and  bitter  orange  peel),  Caryophyllus  (cloves),  Pimenta 
(allspice),  Cinnamomum  (cinnamon),  Sassafras  (sassafras  bark),  Cypripedium 
(lady's  slipper),  Fceniculum  (fennel),  Vanilla  (vanilla),  Cardamomum  (carda- 
mom), Carum  (caraway),  Myristica  (nutmeg),  Hedeoma  (pennyroyal),  Salvia 
(sage),  Sabina  (savine),  Arnica,  and  Zingiber  (ginger).  The  British  Phar- 
macopoeia is  less  lavishly  supplied  with  these  little  used  crude  drugs.  It 
contains,  in  addition  to  those  first  mentioned :  Rosce  Gallicce  Petala  (red 
rose  petals),  Limonis  Cortex  (lemon  peel),  Aurantii  Cortex  Recens  and  Siccatus 
(fresh  and  dried  orange  peel),  Caryophyllum  (cloves),  Carui  Fructus  (caraway 
seeds),  Pimenta  (allspice),  Cinnamomi  Cortex  (cinnamon  bark),  Sassafras  Radix 
(sassafras  root),  Fceniculi  Fructus  (fennel  seeds),  Cardamomi  Semina  (cardamom 
seeds),  Myristica  (nutmeg),  Arnicse  Rhizoma  (arnica  rhizome),  Zingiber  (gin- 
ger), and  Anethi  Fructus  (dill). 

Bitter  Almonds  (Amygdala  Amara,  U.  S.  P.,  B.  P.)  may  be  mentioned 
here,  as,  although  they  contain  no  volatile  oil  in  themselves,  one  is  formed 
from  them  when  they  are  bruised  in  water.  They  contain  a  glucoside, 
amygdalin,  and  a  ferment,  emulsin,  which,  in  the  presence  of  water,  decom- 
poses the  amygdalin  into  dextrose,  prussic  acid,  and  benzaldehyde. 

Amygdalin.  Dextrose.  Prussic  acid.    Benzaldehyde. 

CjoH^NOn    +    3H2O    :  :    2(C6H1206)     +     HCN    +    C7H6O    +    H,O 

The  prussic  acid  and  benzaldehyde,  which  are  probably  in  combination  and 
not  merely  mixed  together,  are  known  as  the  oil  of  bitter  almonds,  which 
is  much  more  poisonous  than  the  other  volatile  oils,  owing  to  its  containing 
prussic  acid.  Emulsin  is  also  contained  in  the  sweet  almond,  but  no  amyg- 
dalin, so  that  no  prussic  acid  is  formed  when  it  is  pounded  in  water.  The 
fixed  oil  of  almonds  is  formed  from  bitter  and  sweet  almonds,  but  contains 
no  prussic  acid.  Laurel  leaves  (Laurocerasi  Folia,  B.  P.),  and  the  bark  of 
the  Virginian  prune,  or  cherry  (Prunus  Virginiana,  U.  S.  P.,  Pruni  Virgini- 


68  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

ance  Cortex,  B.  P.),  also  contain  amygdalin,  or  some  nearly  related  substance, 
and  emulsin,  and  form  benzaldehyde  and  prussic  acid  when  rubbed  up  with 
water.  The  Virginian  cherry  bark  has,  however,  a  more  bitter  taste  than 
the  others,  from  the  presence  of  a  resin  or  some  other  unknown  body. 

The  Volatile  Oils  themselves  are  also  represented  in  unnecessarily  large 
numbers  in  the  pharmacopoeias. 

U.  S.  P. — Oleum  Menthse  Piperitse  (oil  of  peppermint),  01.  Menthse  Viridls 
(spearmint  oil),  Ol.  Gaultherise  (wintergreen),  01.  Lavandulse  Florum  (oil  of 
lavender),  Ol.  Eucalypti  (eucalyptus  oil),  01.  Limonis  Corticis  (oil  of  lemon), 
01.  Aurantii  Corticis  (oil  of  orange  peel),  Oleoresina  Zingiberis  (ginger),  01. 
Amygdalae,  Amarce  (bitter  almonds),  01.  Caryophylli  (oil  of  cloves),  01.  Pimentce 
(oil  of  allspice),  01.  Carui  (caraway  oil),  01.  Cinnamomi  (cinnamon),  01.  Cori- 
andri  (coriander),  01.  Erigerontis  (erigeron  or  fleabane),  01.  Cajuputi  (cajuput), 
01.  Sassafras  (sassafras),  01.  Anisi  (anise),  01.  Fceniculi  (fennel),  01.  Rosmarini 
(rosemary),  01.  Hedeomcp,  (pennyroyal),  01.  Juniperi  (juniper),  01.  Sabince 
(savine),  01.  Rosa*,  (oil,  attar  or  otto  of  roses),  01.  Betulce,  Volatile  (volatile  oil 
of  birch),  01.  Thymi  (thyme),  01.  Myristicce  (nutmeg). 

B.  P. — Oleum  Anethi  (oil  of  dill),  01.  Anisi  (anise),  01.  Cajuputi  (cajuput), 
01.  Carui  (caraway),  OL  Caryophylli  (cloves),  Ol.  Cinnamomi  (cinnamon),  01. 
Coriandri  (coriander),  Ol.  Eucalypti  (eucalyptus),  01.  Lavandulsz  (lavender), 
01.  Limonis  (lemon),  01.  Menthse  Piperitse  (peppermint),  01.  Menthae  Viridis 
(spearmint),  01.  Myristicse  (nutmeg),  01.  Anthemidis  (chamomile),  Ol.  Pimentse 
(allspice),  01.  Rosse  (oil,  attar,  or  otto  of  roses),  01.  Rosmarini  (rosemary). 

The  majority  of  these  oils  resemble  each  other  very  closely  in  their  effects 
and  require  no  special  comment.  Oil  of  roses  is  so  expensive  that  it  is  never 
used  in  medicine,  especially  as  it  has  no  special  advantages  over  the  others. 
The  oils  of  rosemary,  juniper,  and  savine  are  more  irritant  than  the  others, 
and  are  seldom  used.  The  oils  of  wintergreen  and  of  birch  consist  mainly 
of  methyl-salicylate,  and  may  be  used  instead  of  the  other  salicylates. 
Nutmeg  and  mace  oils  are  more  poisonous  than  the  others,  not  from  their 
local  irritant  action  so  much  as  from  their  effects  after  absorption.  Oil  of 
bitter  almonds  contains  a  very  variable  amount  of  prussic  acid  and  therefore 
cannot  be  substituted  for  the  other  volatile  oils,  but  its  preparations  are  so 
dilute  as  to  be  void  of  all  danger. 

The  volatile  oils  themselves  are  comparatively  little  used.  A  single  drop 
may  be  added  to  powders,  pills  or  solutions  to  give  a  pleasant  odor,  and 
their  presence  in  tooth  powders  renders  these  more  or  less  strongly  antiseptic. 
Occasionally  they  are  given  in  cases  of  colic  or  in  chill  by  pouring  a  few 
drops  on  a  piece  of  sugar  which  is  sucked.  The  dose  of  the  volatile  oils  in 
general  is  1-2  drops. 

Spiritus  are  formed  from  many  of  the  volatile  oils  by  dissolving  them 
in  alcohol,  sometimes  with  the  addition  of  water  and  sometimes  with 
some  of  the  crude  drug,  so  that  the  preparation  is  really  a  mixture  of 
tincture  and  spirit.  The  spirits  or  essences  of  the  volatile  oils  are  used 
very  largely  as  flavoring  agents  in  mixtures  for  internal  use,  and  are 
often  added  to  external  applications  to  lend  them  odor.  They  may 
also  be  prescribed  where  alcohol  is  indicated  but  is  distasteful  to  the 
patient ;  the  spirits  of  the  volatile  oils  contain  nearly  double  the 
amount  of  alcohol  in  brandy,  and  have  to  be  diluted  accordingly. 
Any  of  them  may  be  used  as  carminatives,  but  the  spirits  of  pepper- 
mint, cinnamon,  anise  and  lavender  are  more  frequently  used  for  this 
purpose  than  the  others.  Spirit  of  juniper  is  often  given  as  a  diuretic, 
either  alone  or  along  with  other  drugs.  Spirit  of  rosemary  is  generally 
used  externally.  Many  of  the  common  perfumes  are  spirits  of  differ- 


VOLATILE  OIL  SERIES.  69 

ent  volatile  oils ;  thus  eau  de  Cologne  contains  the  oils  of  bergamot, 
lemon,  rosemary,  lavender  and  orange-flower,  along  with  acetic  ether 
and  alcohol. 

The  dose  of  the  spiritus  as  carminatives  is  1-4  c.c.  (15-60  mins.). 
They  are  often  prescribed  along  with  other  stomachics,  such  as  mix 
vomica,  cinchona,  or  the  bitters. 

U.  S.  P. — Spiritus  Amygdala  Amarx,  Spir.  Anisi,  Spir.  Aurantii  Compositus 
(containing  the  oils  of  orange  peel,  lemon,  coriander  and  anise),  Spir.  Cmna- 
momi,  Spir.  Gaultherise,  Spir.  Juniperi,  Spir.  Juniperi  Compositus  (containing 
oils  of  juniper,  caraway  and  fennel.  Dose,  4-8  c.c.,  1-2  fl.  drs.),  Spir.  Lavan- 
dulce,  Spir.  Menthce  Piperitce,  Spir.  Menthce  Viridis. 

Elixir  Aromaticum  and  Elixir  Adjuvans  are  preparations  of  the  Spir.  Aurantii 
Compositus,  which  are  used  exclusively  as  flavors. 

B.  P. — Spiritus  Anisi,  Sp.  Cajuputi,  Sp.  Cinnamomi,  Sp.  Juniperi,  Sp.  La- 
vandulse,  Sp.  Menthse  Piperitce,  Sp.  Myristicze,  Sp.  Rosmarini. 

The  compound  spirit  of  horseradish  (Spir.  Armoracise  Compositus)  is  ob- 
tained by  extracting  the  volatile  oils  of  horseradish,  bitter-orange  peel,  and 
nutmeg  with  dilute  alcohol  and  purifying  them  by  distillation.  Horseradish 
oil,  like  that  of  most  of  the  Cruciferse,  is  a  sulphur  compound,  and  has  a 
peculiarly  hot,  burning  taste.  Dose,  1-2  fl.  drs.  (4-8  c.c.). 

Aquae. — The  volatile  oils  are  very  insoluble  in  water,  but  when  they 
are  shaken  in  it,  enough  remains  in  the  water  to  give  it  the  odor  and 
taste  of  the  oil.  In  the  process  of  obtaining  the  oils  from  the  crude 
drugs  by  distillation,  some  oil  is  held  by  the  water,  and  a  number  of 
these  waters  (aquae)  are  contained  in  the  pharmacopoeias.  They  are  used 
as  substitutes  for  distilled  water  in  making  up  prescriptions,  the  small 
quantity  of  volatile  oil  serving  merely  to  give  a  pleasant  odor  and  taste. 

U.  S.  P. — Aqua  Anisi,  Aq.  Aurantii  Flor.  and  Aq.  Aurantii  Florum  Fortior 
(the  latter  containing  twice  as  much  volatile  oil  as  the  former),  Aq.  Cinna- 
momi, Aq.  Fceniculi,  Aq.  Menth.  Piperitse,  Aq.  Menth.  Viridis,  Aq.  Rosas, 
Aq.  Rosas  Fortior  (the  latter  twice  as  strong  as  the  ordinarily  used  Aq. 
Rosse). 

B.  P. — Aqua  Anethi,  Aq.  Anisi,  Aq.  Aurantii  Florum,  Aq.  Carui,  Aq.  Cin- 
namomi, Aq.  Fceniculi,  Aq.  Laurocerasi  (laurel  water,  containing  prussic  acid 
and  benzaldehyde),  Aq.  Menthse  Piperitse,  Aq.  Menthse  Viridis,  Aq.  Pimentse, 
Aq.  Rosse,  Aq.  Sambuci. 

Another  preparation  containing  a  volatile  oil  merely  as  a  flavoring  ingredient 
is  Unguentum  Aquce  Rosce  (cold  cream),  U.  S.  P.,  B.  P. 

Some  of  the  preparations  containing  volatile  oils  are  derived  not 
from  the  oil  itself,  but  from  the  crude  drug,  and  therefore  contain 
non-volatile  substances  which  are  generally  absent  from  the  prepara- 
tions already  mentioned.  As  a  general  rule  these  non-volatile  bodies 
are  inactive,  but  in  some  cases,  bitters  or  resins  are  contained  in  the 
preparations,  and  may  influence  their  action.  Thus  a  bitter  glucoside, 
hesperidin,  is  found  in  the  orange  peel,  and  is  present  in  the  prepara- 
tions formed  directly  from  it,  while  it  is  absent  from  those  formed  from 
the  volatile  oil.  Ginger  contains  a  resin  of  hot,  burning  taste,  which 
increases  the  carminative  action  of  the  oil.  Cinnamon  contains  some 
tannic  acid,  which  passes  over  in  the  tincture,  while  a  fixed  oil  is  con- 
tained in  cardamom.  Arnica  contains  a  bitter  substance,  arnicin ; 


70  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

calamus,  a  bitter,  acorin,  in  addition  to  a  volatile  oil ;  cascarilla,  a 
bitter  principle,  cascarillin,  along  with  another  oil.  Preparations 
which  contain  a  bitter  substance  in  addition  to  a  volatile  oil,  are  often 
classed  as  aromatic  bitters  along  with  the  Pepper  series. 

Among  the  preparations  formed  from  the  crude  drugs  are  the  Syrups, 
which  are  used  exclusively  as  flavoring  agents. 

U.  S.  P. — Syrupy s  Aurantii  Florum,  Syr.  Amygdalae,  Syr.  Aurantii,  Syr. 
Rosse,  Syr.  Zingiberis,  Syr.  Pruni  Virginianse. 

B.  P. — Syrupus  Aromaticus  (containing  tincture  of  orange  and  cinnamon 
water),  Syr.  Aurantii,  Syr.  Aurantii  Floris,  Syr.  Limonis,  Syr.  Pruni  Virgini- 
anse, Syr.  Rosse,  Syr.  Zingiberis.  Dose  of  syrups,  B.  P.,  2-4  c.c.  (£-1  fl.  dr.). 

The  Tinctures  are  used  for  the  same  purposes  as  the  spirits  of  the 
pure  oils,  and  in  the  same  dose,  1-4  c.c.  (15-60  mins.).  The  tinctures 
of  arnica  are  employed  externally  as  applications  to  bruised  surfaces 
and  in  similar  conditions,  but  they  have  no  more  effect  than  other 
preparations,  although  they  are  popularly  regarded  as  specifics. 

U.  S.  P. — Tinctura  Arnicas,  Tinct.  Aurantii  Amari,  Tinct.  Aurantii  Dulcis, 
Tinct.  Limonis  Corticis,  Tinct.  Cardamomi,  Tinct.  Cardamomi  Composita 
(containing  cardamom,  cinnamon,  caraway),  Tinct.  Cinnamomi,  Tinct.  Lavan- 
dulse  Composita  (oils  of  lavender,  rosemary,  cinnamon,  cloves,  nutmeg),  Tinct. 
Vanillse,  Tinct.  Zingiberis. 

B.  P. — Tinctura  Arnicce,  Tinct.  Aurantii,  Tinct.  Cardamomi  Composita  (con- 
taining cardamom,  caraway,  cinnamon  and  raisins),  Tinct.  Cinnamomi, 
Tinct.  Lavandulse  Composita  (lavender,  rosemary,  cinnamon,  nutmeg),  Tinct. 
Limonis,  Tinct.  Pruni  Virginianse,  Tinct.  Zingiberis,  Tinct.  Cascarillss. 

Fluid  Extracts  of  the  volatile  oil  series. 

U.  S.  P. — Fluidextractum  Aurantii  Amari,  1-2  c.c.  (15-30  mins.). 

Fluidextractum  Rosce,  4-8  c.c.  (1-2  fl.  drs.). 

Fluidextractum  Calami,  0.5-1.3  c.c.  (8-20  mins.). 

Fluidextractum  Sabince,  0.2-0. 5  c.c.  (3-8  mins.). 

Fluidextractum  Pruni  Virginiance,  2—4  c.c.  (£— 1  fl.  dr.). 

Fluidextractum  Zingiberis,  0.5-1.3  c.c.  (8-20  mins.). 

Fluidextractum  Aromaticum,  0.5-1.3  c.c.  (8-20  mins.),  from  aromatic  powder. 

The  only  fluid  extracts  at  all  extensively  used  are  the  last  three. 

Infusions. 

U.  S.  P. — Infusum  Pruni  Virginianse. 

B.  P. — Infusum  Aurantii. 

Infusum  Aurantii  Compositum  (formed  from  bitter  orange  peel,  fresh  lemon 
peel  and  cloves). 

Infusum   Caryophylli. 

Infusum  Rosse  Acidum  (containing  sulphuric  acid). 

Infusum  Cascarillss. 

These  infusions  are  given  in  doses  of  £-1  fl.  oz.  (15-30  c.c.)  and  may  be 
used  instead  of  the  medicated  waters  (aquae). 

Other  Preparations. 

Extractum  Anthemidis  (B.  P.),  0.1-0.5  G.  (2-8  grs.). 

Confectio  Roste  Gallicse  (B.  P. ). 

These  last  two  preparations  are  used  almost  exclusively  as  cohesive  bases 
for  pills. 

Pulvis  Aromaticus  (U.  S.  P.)  contains  cinnamon,  cardamom,  ginger,  and 
nutmeg  in  powder,  and  is  a  useful  carminative  in  doses  of  0.3-2  G.  (5-30  grs.). 

Pulvis  Cinnamomi  Compositus  (B.  P.)  contains  cinnamon,  cardamom  and 
ginger,  and  is  used  as  a  carminative  in  doses  of  10-40  grs. 

Unguentum  Eucalypti  (B.  P.). 


VOLATILE  OIL  SERIES.  71 

Pure  Principles  used  as  flavors  : 

Safrolum  (U.  S.  P.),  safrol  (C6H3-C3H5-OOCH?),  a  pure  principle  found  in 
sassafras  and  other  volatile  oils,  possesses  an  odor  like  sassafras.  It  is  a  colorless 
or  faintly  yellow  liquid,  soluble  in  alcohol  and  ether.  Dose,  0.3  c.c.  (5  mins.). 

Vanilliimm  (U.  S.  P.),  vanillin  (C6H3-OH-OCH,-COH),  occurs  in  vanilla  and 
is  also  made  synthetically.  It  forms  white  needle  crystals,  slightly  soluble  in 
water,  easily  soluble  in  alcohol  and  ether,  and  possesses  the  odor  and  taste  of 
vanilla.  Dose,  0.03  G.  (£  gr.). 

Benzaldehydum  (U.  S.  P.),  benzaldehyde  (C6H5COH),  occurs  in  the  oil  of 
bitter  almonds,  and  is  also  made  artificially.  It  is  a  colorless  fluid  with  the  odor 
and  taste  of  bitter  almond  oil,  very  slightly  soluble  in  water,  but  freely  miscible 
with  alcohol.  Dose,  0.03  c.c.  (J  min.). 

Cinnaldehydum  (U.  S.  P.),  cinnamic  aledhyde  (C6H5CH  :CH-COH),  is 
nearly  identical  with  cinnamon  oil  and  forms  a  colorless  liquid  with  the  odor  of 
cinnamon  and  a  hot,  burning  taste.  Dose,  0.05  c.c.  (1  min.). 

Eugenol  (U.  S.  P.),  a  phenol  (C6H3OH-OCH3-C3H5)  obtained  from  oil  of 
cloves  and  other  oils,  and  forming  a  colorless  liquid  with  an  odor  like  cloves,  and 
a  hot,  burning  taste.  Dose,  0.2  c.c.  (3  mins.). 

These  principles  are  used  exclusively  to  give  flavor  and  odor. 

Several  pure  substances  which  have  been  isolated  from  the  volatile 
oils  and  introduced  into  therapeutics  (eucalyptol,  menthol,  thymol)  will 
be  mentioned  later.  (See  index.) 

A  number  of  other  volatile  substances  are  used  locally  in  medicine 
for  the  same  purpose  as  the  volatile  oils,  although  they  are  classified  in 
other  groups  owing  to  their  possessing  other  properties  which  are  not 
shared  by  the  oils.  Among  these  may  be  mentioned  especially  the 
preparations  of  chloroform  (aqua,  emulsum,  spiritus,  linimentum),  the 
simple  and  compound  spirits  of  ether,  and  acetic  ether.  These  are  used 
largely  for  the  same  purposes  as  the  volatile  oil  preparations,  and  when 
administered  in  moderate  quantities  do  not  cause  any  further  effects. 
The  preparations  of  alcohol  known  as  spirits,  or  liqueurs,  or  essences, 
contain  volatile  oils  —  Curacoa,  Cherry  water  (Kirch  wasser),  Kummel, 
Essence  of  Mint,  etc. — and  the  simpler  spirits,  Brandy,  Whiskey, 
Rum,  Gin,  and  the  wines  contain  bodies  known  as  oenanthic  ethers, 
which  probably  act  in  a  similar  way. 

BlBLIOGKAPHY. 

Bvcholtz.     Arch.  f.  exp.  Path.  u.  Pharm.,  iv.,  p.  1.     (Antiseptic  action.) 
Bokorny.     Arch.  f.  d.  ges.  Physiol.,  Ixxiii.,  p.  555. 
Binz.     Arch.  f.  exp.  Path.  u.  Pharm.,  v.,  p.  109  ;  viii.,  p.  50. 
Pohl     Ibid.,  xxv.,  p.  51. 

Batetti.     Trav.  du  Labor,  de  Therapeut.  de  Geneve,  iii.,  p.  197. 
Brandl,  Scanzoni,  Farnsteiner.    Ztschr.  f.  Biol.,  xxix.,  p.  277,  xxxiii.,  pp.  462,  475. 
(Action  on  absorption  from  stomach  and  bowel ;  compare  papers  by  Pawlow  and  his 
pupils.     Arch,  des  Scienc.  biolog.,  ii.  and  iii.) 

Heffter.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv.,  p.  342.     (Saffrol,  etc.) 

Winternitz.     Ibid.,  xlv.,  p.  163. 

Fromm  u.  Hildebrandt.     Ztschr.  f.  physiol.  Chem.,  xxxiii.,  p.  579 ;  xxxvi.,  p.  441. 

Lindemann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlii.,  p.  356  ;  Ztschr.  f.  Biol.,  xxxix.,  p.  1. 

Culhbert  Hall.     Eucalyptus  Oils.     Thesis,  Sydney,  1904. 

Lapin.     Inaug.  Diss.,  Dorpat,  1893.     (Ol.  Menth.  pip.) 

Fleischmann.  Untersuch.  d.  Wiirzburger  pharmakol.  Institut,  111.,  p.  50.    (Turpentine. ) 

Robert.     Centralbl.  f.  d.  med.  Wissen.,  1877,  p.  129.     (Turpentine.) 

Hare.     Medical  News,  li.,  p.  593.     (Turpentine.) 

Pallop.     Inaug.  Diss.,  Dorpat,  1889.     (Turpentine.) 

Wallace.     J.  of  Exp.  Med.,  vi.     (Nutmeg.) 


72  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

2.    Pepper  Group. 

Several  drugs  which  act  as  carminatives  like  the  volatile  oils,  but  which 
differ  from  them  in  the  nature  of  their  active  constituents,  may  be  mentioned 
here. 

Black  Pepper  contains  a  weakly  basic  substance,  Piperine  (which  is  broken 
up  by  caustic  alkalies  into  Piperidine  and  Piperinic  acid),  in  addition  to  a 
volatile  oil  and  a  bitter  pungent  resin.  According  to  Buchheim  a  second 
base,  Chavicine,  also  exists  in  it  and  can  be  decomposed  into  Piperidine  and 
Chavicic  acid.  Piperine  is  insoluble  in  water,  and  has  therefore  no  taste 
when  absolutely  pure,  but  is  hot  and  pungent  to  the  taste  when  it  is  taken  in 
solution. 

Pyrethrum,  or  pellitory,  contains  similar  constituents,  volatile  oil,  resin 
and  Pyrethrine,  which  is  decomposed  into  Piperidine  and  Pyrethric  acid 
(Buchheim). 

The  unstable  alkaloid,  Sedine,  of  Sedum  acre  (biting  stonecrop),  resembles 
the  pepper  alkaloids  in  its  effects,  but  has  not  been  accurately  examined  as 
yet. 

Capsicum,  or  Cayenne  pepper,  contains  a  number  of  ill-defined,  non-vola- 
tile bodies,  which  have  been  termed  Capsicol,  Capsaicin,  Capsicin,  etc.,  but 
of  which  little  or  nothing  is  known  accurately.  As  it  has  no  volatile  oil,  it 
differs  entirely  from  the  other  members  of  the  series,  but  it  acts  similarly  in 
the  stomach,  and  is  used  frequently  as  an  irritating  carminative. 

Ginger  might  also  be  included  here,  as  it  owes  its  pungency  in  part  to  the 
presence  of  a  resin  along  with  the  volatile  oil. 

The  volatile  oils  derived  from  the  CruciferaB  differ  from  the  others  in  con- 
taining sulphur,  and  in  possessing  a  much  more  irritating  action.  Thus  the 
volatile  oil  of  mustard  might  be  treated  of  along  with  the  peppers  rather 
than  with  the  other  volatile  carminatives,  but  mustard  is  used  in  medicine 
only  as  a  skin  irritant,  and  will  be  taken  up  in  that  connection  (see  page  89). 
The  horseradish  (Armoracia,  B.  P.)  and  the  formerly  official  scurvy- grass 
(Cochlearia  officinalis)  are  used  as  carminatives,  and  owe  their  activity  to 
their  containing  similar  or  identical  sulphur  compounds. 

These  drugs  differ  from  the  volatile  oils  only  in  being  more  irritant  when 
applied  to  the  skin  and  alimentary  canal.  The  absorption  of  large  quanti- 
ties has  led  to  inflammation  of  the  kidney  in  some  instances. 

Pepper  and  capsicum  are  largely  used  as  condiments,  and  are  compara- 
tively seldom  prescribed  in  therapeutics.  Both  are  used  in  domestic  medi- 
cine as  skin  irritants,  and  capsicum  is  prescribed  where  a  strong  stomachic 
irritant  is  required.  The  tincture  has  been  employed  in  chronic  alcoholism 
in  order  to  provide  a  substitute  for  the  local  irritant  effects  of  spirits  in  the 
stomach.  Ginger  preparations  are  added  to  other  remedies  as  flavoring 
agents,  the  syrup  being  generally  used,  and  they  are  also  among  the  best  of 
the  carminatives.  The  lozenges  are  prescribed  in  chronic  inflammatory  con- 
ditions of  the  pharynx  and  larynx.  Pyrethrum  is  rarely  employed.  Piper- 
ine has  been  advised  in  malaria  as  a  substitute  for,  or  adjuvant  to  quinine, 
but  has  fallen  into  disuse.  Pepper  has  been  administered  internally  as  a 
genito-urinary  disinfectant  and  stimulant. 

PREPARATIONS. 

Piper  (U.  S.  P.),  Piper  Nigrum  (B.  P.),  black  pepper,  the  unripe  fruit  of 
Piper  Nigrum. 

Oleoresina  Piperis  (U.  S.  P.),  0.03-0.1  c.c.  (|-2  mins.). 

Piperinum  (U.  S.  P.),  0.1-0.5  G.    (2-3  grs.). 

Confectio  Piperis  (B.  P.),  60-120  grs. 

Pyrethrum  (U.  S.  P.),  Pyrethri  Radix  (B.  P.),  pellitory,  the  root  of  Ana- 
cyclus  Pyrethum. 

Tinctura  Pyrethri  (U.  S.  P.,  B.  P.). 


VOLATILE  OIL  SERIES.  73 

Zingiber  (TJ.  S.  P.,  B.  P.),  ginger,  the  rhizome  of  Zingiber  officinale. 

Syrupus  Zingiberis  (U.  S.  P.,  B.  P.),  4-8  c.c.  (1-2  fl.  drs.). 

Tinctura  Zingiberis  (U.  S.  P.,  B.  P.),  2-4  c.c.  (£-1  fl.  dr.). 

Extractum  Zingiberis  Fluidum  (U.  S.  P.),  0.5-1  c.c.  (5-15  mins.). 

Oleoresina  Zingiberis  (U.  S.  P.),  0.05-0.1  c.c.  (1-2  mins.). 

Capsicum,  Cayenne  pepper,  chillies,  the  fruit  of  Capsicum  fastigiatum 
(U.  S.  P.);  Capsici  Fructus,  the  dried  fruit  of  Capsicum  minimum  (B.  P.). 

Tinctura  Capsici  (U.  S.  P.,  B.  P.),  1-2  c.  c.  (15-30  mins.). 

Oleoresina  Capsici  (U.  S.  P.),  0.01-0.05  c.c.  (J-l  min.). 

Fluidextractum  Capsici  (U.  S.  P.),  0.03-0.1  c.c.  ($-2  mins.). 

Emplastrum  Capsici  (U.  S.  P.). 

Unguentum  Capsici  (B.  P.). 

Armoraciae  Radix  (B.  P.),  horseradish  root,  the  fresh  root  of  Cochlearia 
Armoracia. 

Spiritus  Armoracix  Compositus  (B.  P.),  1-2  fl.  drs.     (See  p.  68.) 

Piper  Methlsticum,  or  Kava  Kava,  is  used  in  the  South  Sea  Islands  to 
prepare  an  intoxicating  liquor,  which  according  to  Kesteven,  differs  from 
the  alcoholic  preparations  in  producing  marked  muscular  weakness  without 
affecting  the  mental  powers.  Other  observers  state,  however,  that  it  causes 
confusion  and  sleep  very  much  as  alcohol  does.  Its  local  action  resembles 
that  of  pepper,  and  like  it,  it  has  been  advised  in  gonorrhoea.  Its  virtues 
seem  to  reside  in  two  resinous  bodies. 

BIBLIOGRAPHY. 

Buchheim.     Arch.  f.  exp.  Path.  u.  Pharm.,  v.,  p.  455. 

Jungst.     Ibid.,  xxiv.,  p.  315. 

Hogyes.     Ibid.,  ix.,  p.  117. 

Kesteven.     Practitioner,  xxviii.,  p.  199. 

Lewin.     Berlin,  klin.  Woch.,  1886,  p.  7. 

Cerna.     Therapeut.  Gazette,  1891,  p.  7. 

3.   Malodorous  Volatile  Oils. 

Some  of  the  volatile  oils  differ  from  the  others  in  possessing  an  odor 
which  is  disagreeable  and  nauseating  to  most  people,  although  not  to 
all.  The  best  known  of  these  are  the  Oils  of  Asafcetida  and  Valerian. 
The  former  occurs  along  with  resins  and  gums  exuding  from  some 
species  of  Ferula,  and  contains  several  organic  sulphur  compounds,  to 
which  it  owes  its  odor.  Oil  of  Valerian,1  from  Valeriana  officinalis, 
is  almost  without  odor  when  freshly  distilled,  but  when  kept  for  some 
time  and  exposed  to  the  air,  it  assumes  a  somewhat  unpleasant,  pene- 
trating odor.  It  contains  two  terpenes,  borneo-camphor,  and  numer- 
ous esters  of  formic,  acetic  and  valerianic  acid.  While  both  of  these 
oils  are  generally  regarded  as  possessing  very  unpleasant  odors,  asa- 
foatida  is  used  in  India  as  a  condiment,  and  valerian  was  formerly  used 
in  England  as  a  perfume.  Another  species  of  Ferula  which  is  in- 
cluded in  the  pharmacopeias,  but  of  which  little  is  known,  is  Sumbul, 
the  root  of  Ferula  Sumbul.  It  has  a  strong  musk-like  odor,  and  is 
sometimes  used  to  adulterate  musk. 

Asafetida  and  valerian  are  used  in  hysterical  affections,  and  the 
benefits  accruing  from  their  administration  have  generally  been  at- 
tributed to  the  mental  impression  produced  by  their  unpleasant  odor 
and  taste,  and  not  to  any  action  they  produce  after  absorption. 
1  Sikorska,  These  de  Geneve,  1899. 


74  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

But  Kionka l  states  that  valerian,  in  small  doses,  has  a  definite 
stimulating  action  on  the  psychical  functions  and  the  circulation,  and 
that  this  is  due  to  the  presence  of  certain  valerianic  esters  in  the  oil. 
Some  artificial  compounds  ( Valyl)  possessing  similar  properties  have 
also  been  formed.  The  ordinary  valerianic  salts  have  no  further 
effects  than  other  salts  of  the  acetic  acid  series,  so  that  it  is  quite  irra- 
tional to  use  such  bodies  as  valerianate  of  quinine  for  their  action  in 
hysteria. 

Asafoetida  is  also  used  like  the  other  volatile  oils  as  a  carminative 
and  as  an  expectorant,  and  the  emulsion  is  given  by  the  mouth  or  in 
an  enema  to  relieve  abdominal  distention. 

PREPARATIONS. 

-  Asafoetida  (U.  S.  P.),  a  mixture  of  volatile  oil,  gum,  and  resin  from  Ferula 
foetida. 

Emulsum  Asafcetidse,  15-30  c.c.  (|-1  fl.  oz.). 

Pilulx  Asafcetidse,  1-3  pills. 

Tinctura  Asafcetidce,  1—2  c.c.  (15—30  mins.). 

Asafetida  (B.  P.),  a  gum-resin  obtained  from  the  root  of  Ferula  foetida  and 
probably  other  species. 

Tinctura  Asafetidce,  £— 1  fl.  dr. 

Pilula  Aloes  et  Asafetidce,  4-8  grs. 

Pilula  Galbani  Composite/,,  4-8  grs. 

Spiritus  Ammonive  Fetidus,  20-40  mins.  for  repeated  administration  ;  for  a 
single  administration  60-90  mins. 

Valeriana  (U.  S.  P.),  Valerianse  Radix  (B.  P,),  valerian,  the  rhizome  and 
roots  of  Valeriana  officinalis. 

Fluidextractum  Valeriance  (U.  S.  P.),  2-4  c.c.  (|-1  fl.  dr.). 

Tinctura  Valerians  (U.  S.  P.),  5-10    c.c.  (1-3  fl.  drs.). 

Tinctura  Valeriance  Ammoniata  (U.  S.  P.),  5-10  c.c.  (1-3  fl.  drs.). 

Tinctura  Valeriance,  Ammoniata  (B.  P.),  £-1  fl.  dr. 

Sumbul  (U.  S.  P.),  Sumbul  Kadix  (B.  P.),  the  root  of  Ferula  Sumbul. 

Extractum  Sumbul  (U.  S.  P.),  0.25  G.  (4  grs.). 

Fluidextractum  Sumbul  (U.  S.  P.),  2  c.c.  (30  mins.). 

Tinctura  Sumbul  (B.  P. ),  £-1  fl.  dr. 

4.  Volatile  Oils  Used  as  Genito -urinary  Disinfectants. 

Another  group  of  volatile  oils  is  used  chiefly  for  genito-urinary  dis- 
infection. The  best  known  of  these  are  the  Oils  of  Copaiba,  Cubebs  and 
Sandalwood,  which  resemble  each  other  closely  in  character.  Oil  of 
cubebs  and  oil  of  copaiba  contain  a  large  proportion  of  sesquiterpene 
(C15H24),  and  the  oil  of  sandalwood  has  two  oxidized  substances  (san- 
tolol  and  santalal),  which  can  be  reduced  to  a  sesquiterpene  identical 
with  that  of  copaiba.  In  copaiba  the  volatile  oil  is  associated  with 
one  or  more  resinous  acids,  and  in  cubebs  there  is  in  addition  to  resi- 
nous acids  a  bitter  substance,  Cubebin,  which  is  not  absorbed  from  the 
stomach  and  bowel,  however,  and  is  entirely,  inactive.  Cubebs  and 
copaiba  have  long  been  used  as  genito-urinary  disinfectants,  while 
sandalwood  oil  is  a  more  recent  addition  to  the  group,  which  is  less 

1  Arch.  Internat.  de  Pharmacodyn.,  xiii.,  p.  215. 


VOLATILE  OIL  SERIES.  75 

disagreeable  to  take  and  has  less  tendency  to  disturb  the  digestion.1 
The  oils  have  the  ordinary  effects  on  the  skin,  stomach  and  intestine, 
are  absorbed,  and  are  excreted  partly  by  the  lungs,  but  chiefly  by  the 
kidneys  in  combination  with  glycuronic  acid  ;  some  oil  is  unchanged, 
some  is  partially  oxidized  in  the  tissues. 

The  products  of  the  oils  excreted  in  the  urine  appear  to  have  some 
antiseptic  action,  for  the  urine  of  persons  treated  with  them  putrefies 
more  slowly  than  ordinary  urine  and  the  growth  of  many  of  the  more 
common  germs  is  somewhat  retarded  by  it.  On  the  other  hand  there 
seems  some  question  as  to  how  far  it  is  destructive  to  the  gonococcus, 
which  sometimes  grows  readily  in  culture  media  made  up  with  such 
urine  instead  of  water.  Winternitz  therefore  attributes  the  undoubted 
therapeutic  efficacy  of  these  oils  to  their  lessening  the  inflammatory 
exudate  rather  than  to  their  antiseptic  action,  without  denying  that  the 
latter  may  also  be  of  some  importance.  In  large  quantities,  these 
oils  cause  irritation  in  the  bladder  and  urethra,  which  leads  to  a  con- 
stant desire  to  micturate,  and  to  much  pain  and  difficulty  in  doing  so ; 
sometimes  the  pain  is  so  great  as  to  lead  to  complete  retention.  When 
the  urethra  or  bladder  is  in  a  state  of  inflammation,  these  symptoms 
are  produced  by  even  small  doses,  so  that  these  oils  are  generally 
avoided  in  the  acute  stages  of  inflammation,  and  only  given  later  when 
the  disease  has  passed  into  the  subacute  or  chronic  stage.  They  are 
used  in  some  inflammatory  affections  of  the  bladder,  but  much  more 
extensively  in  gonorrhoea. 

Copaiba  and  cubebs  both  contain  resinous  acids  in  addition  to  the 
volatile  oil,  and  these  possess  considerable  diuretic  powers,  and  are 
also  credited,  along  with  the  oils,  with  some  action  on  the  bronchial 
mucous  membrane,  so  that  they  often  form  constituents  of  "  expec- 
torant" mixtures,  prescribed  to  lessen  the  secretion  of  the  bronchi. 
These  resins  are  excreted  in  the  urine,  and  are  precipitated  by  the  ad- 
dition of  acids ;  when  the  nitric  acid  tests  for  albumin  are  employed 
after  copaiba,  a  precipitate  is  accordingly  obtained,  and  may  be  mis- 
taken for  albumin,  but  can  easily  be  distinguished  from  it  by  the  addi- 
tion of  alcohol,  which  redissolves  the  resin  but  not  the  proteid.  The 
urine  is  often  found  to  reduce  Fehling's  solution,  in  some  cases  ap- 
parently from  the  presence  of  sugar,  in  others  from  the  glycuronic  acid 
combined  with  the  oil.  The  oil  of  sandalwood  is  excreted  more 
rapidly  than  the  others.  Copaiba  and  cubebs  are  less  irritant  to  the 
stomach  than  many  of  the  other  volatile  oils,  but  after  their  prolonged 
administration  (especially  in  the  case  of  copaiba)  symptoms  of  gastric 
disturbance  sometimes  appear  in  loss  of  appetite  and  uneasiness  in  the 
stomach.  Sandalwood  oil  is  said  to  be  less  irritant  than  the  others. 
Occasionally  skin  eruptions  occur  after  the  use  of  these  oils ;  they  are 
generally  of  the  nature  of  urticaria,  sometimes  of  erythema  nodosum, 
and  only  very  rarely  is  eczema  seen.  The  cause  of  these  skin  erup- 
tions is  unknown,  but  they  may  be  due  to  the  gastric  disturbance. 

1  The  ideal  genito-urinary  disinfectant  of  this  series  ought  to  be  well  borne  by  the 
stomach  and  bowel,  and  ought  to  be  excreted  mainly  by  the  kidneys  in  a  fairly  strong 
combination  with  glycuronic  acid,  as,  if  the  latter  is  easily  split  off  in  the  urine,  it  is 
liable  to  act  as  a  culture  medium  for  bacteria.  (Schmiedeberg. ) 


76  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

PREPARATIONS. 

Copaiba  (U.  S.  P.,  B.  P.),  Balsam  of  Copaiba,  Copaiva,  the  oleoresin  of 
Copaiba  Langsdorffii  and  of  other  species  of  Copaifera.  Dose,  0.5-1.3  c.c. 
(10-20  mins.);  B.  P.,  £-1  fl.  dr. 

OLEUM  COPAIBA  (U.  S.  P.,  B.  P. ),  the  oil  freed  from  the  resin  by  distilla- 
tion, 0.5-1  c.c.  (10-15  mins.). 

Cubeba  (U.  S.  P.),  Cubebae  Fructus  (B.  P.),  Cubebs,  the  unripe  fruit  of 
Piper  Cubeba,  2-8  G.  (30-120  grs.)  in  powder. 

Fluidextractum  Cubebce  (U.  S.  P.),  0.5-2  c.c.  (10-30  mins.). 

OLEORESINA  CUBEBAE  (U.  S.  P.),  0.5-1  c.c.  (10-15  mins.). 

Tinctura  Cubebn  (B.  P.),  4-8  c.c.  (1-2  fl.  drs.). 

OLEUM  CUBEBA  (U.  S.  P.,  B.  P.),  0.5-1  c  c.  (10-15  mins.). 

Trochisci  Cubebse  (U   S.  P.). 

Oleum  Santali  (U.  S.  P.,  B.  P.),  Sandalwood  oil,  distilled  from  the  wood 
of  Santalum  Album.  Dose,  0.5-1  c.c.  (10-15  mins.). 

Therapeutic  Uses. — As  has  been  mentioned,  these  drugs  find  their 
most  extensive  application  in  the  subacute  stages  of  cystitis  and  gonor- 
rhoea.1 They  are  also  used  in  bronchial  disease  with  an  excessive  flow 
of  mucopurulent  secretion  ;  less  often  copaiba  is  prescribed  along  with 
other  diuretics  to  promote  the  secretion  of  urine.  The  cubeb  lozenges 
are  sucked  in  hoarseness  and  relaxed  sore  throat,  and  often  give  relief 
owing  to  the  pungent  stimulating  action. 

In  gonorrhoea  the  therapeutic  agent  is  undoubtedly  the  volatile  oil, 
the  resin  having  little  or  no  antiseptic  action.  The  oils  and  the  oleo- 
resins  are  often  administered  in  capsules,  as  they  have  an  unpleasant 
odor  and  taste,  especially  those  of  copaiba.  They  may  also  be  given  as 
emulsions,  and  cubebs  is  sometimes  prescribed  as  a  powder  suspended 
in  mucilage. 

Several  other  oils  have  been  used  as  substitutes  for  Copaiba  and  Cubebs. 
Among  these  may  be  mentioned  Gurjun  Balsam,  which  is  obtained  from 
Dipterocarpus  alatus,  and  contains  a  sesquiterpene  and  a  resin.  It  has  been 
used  in  gonorrhoea  and  as  a  local  application  in  leprosy. 

Matico,  the  dried  tops  of  Piper  angustifolium,  which  contains  a  volatile 
oil,  resin  and  acid,  has  also  been  used  in  gonorrhoea  to  some  extent. 

Its  pharmacopoeial  preparation  is 

Fluidextractum  Matico  (U.  S.  P.),  1-3  c.c.  (15-45  mins.) 

BIBLIOGRAPHY. 

Bernatzik.     Vierteljahrschrift  f.  prakt.  Heilkunde,  Ixxxi.,  p.  9,  and  c.,  p.  239. 

Schmidt.     Arch.  d.  Pharm.,  cxci.,  p.  1. 

Quincke.     Arch.  f.  exp.  Path..u.  Pharm.,  xvii.,  p.  273. 

Heffter.     Ibid.,  xxxv.,  p.  369. 

Winternitz.     Ibid.,  xlv.,  p.  163. 

Karo.     Ibid.,  xlvi.,  p.  242. 

Hildebrandt.     Ztschr.  f.  physiol.  Chem.,  xxxvi.,  p.  442. 

Sachs.     Wiener,  klin.  Woch.,  xv.,  p.  442.  ^ 

See  also  the  bibliography  of  the  volatile  oils  in  general. 

1  Other  remedies  which  have  some  reputation  in  these  conditions  are  urotropin  and 
the  salicylic  compounds. 


VOLATILE  OIL  SERIES.  77 

5.     Uva  Ursi  (Arbutin). 

A  number  of  drugs  which  are  used  for  almost  the  same  purposes  as  the 
cubebs  series,  but  which  do  not  all  owe  their  activity  to  volatile  oils,  may 
be  mentioned  here. 

Uva  Ursi. — The  leaves  of  the  bearberry,  Arctostaphylos  Uva-Ursi,  and  of 
allied  plants  contain  two  glucosides,  Arbutin  and  Methylarbutin,  along  with 
large  quantities  of  tannin,  an  inactive  glucoside,  Ericolin,  and  a  neutral  in- 
soluble body,  Urson.  These  glucosides  are  decomposed  by  the  action  of 
acids  or  of  emulsin  into  glucose  and  hydroquinone  or  methylhydroquinone, 
bodies  of  the  benzol  series.  A  part  of  the  arbutin  administered  in  thera- 
peutics seems  to  undergo  this  decomposition  in  the  body,  but  most  of  it  is 
eliminated  by  the  kidneys  unchanged.  It  is  possible  that  the  small  quantity 
of  hydroquinone  and  methylhydroquinone  which  appears  in  the  urine  is 
formed  from  arbutin  by  the  bacteria  of  the  intestine,  and  not  by  the  activity 
of  the  tissues. 

Uva  ursi  is  found  to  have  some  diuretic  action,  which  is  obviously  due  to 
its  acting  on  the  renal  epithelium,  and  the  urine  is  found  to  undergo 
putrefaction  much  more  slowly  than  usual.  This  was  at  one  time  believed 
to  be  due  to  the  formation  of  hydroquinone,  but  it  seems  more  likely  that 
arbutin  itself  is  a  slight  stimulant  to  the  renal  cells,  and  that  it  is  also 
weakly  antiseptic.  It  is  still  undecided  how  far  the  other  constituents  of 
uva  ursi  are  active,  but  there  is  little  doubt  that  the  arbutin  and  methyl- 
arbutin  are  the  chief  principles. 

The  urine  is  often  dark  in  color  after  uva  ursi  or  arbutin,  and  this  tint 
deepens  when  it  is  allowed  to  stand  and  undergo  putrefaction.  The  color- 
ation is  due  to  the  hydroquinone,  which  is  subject  to  further  oxidation,  and 
forms  brownish-green  pigments  similar  to  those  seen  in  the  urine  after 
carbolic  acid  and  its  allies.  When  decomposition  of  the  urine  occurs  in  the 
bladder,  as  in  cystitis,  the  urine  may  have  this  dark  color  when  passed.  In 
these  cases  probably  less  of  the  arbutin  escapes  undecomposed,  but  this  has 
not  been  demonstrated. 

Large  quantities  of  uva  ursi  cause  nausea,  vomiting  and  diarrhoea,  but 
Lewin  states  that  this  disturbance  of  the  alimentary  canal  may  be  avoided 
by  filtering  the  watery  preparations  through  animal  charcoal,  or  by  admin- 
istering the  glucosides  instead  of  the  cruder  preparations. 

Buchu,  the  leaves  of  several  species  of  Barosma,  contain  a  volatile  oil, 
one  constituent  of  which  is  a  camphor  body,  Diosphenol.  This  volatile  oil 
is  absorbed  and  is  excreted  by  the  kidneys,  and  renders  the  urine  slightly 
antiseptic.  It  does  not  increase  the  renal  activity  appreciably. 

Pichi,  the  twigs  of  Fabiana  imbricata,  contains  a  resinous  acid,  a  gluco- 
side and  traces  of  an  alkaloid,  none  of  which  have  been  satisfactorily  exam- 
ined. It  has  been  found  of  benefit  in  the  same  conditions  as  Buchu  and 
Uva  Ursi. 

Zea,  or  corn  silk,  contains  a  resinous  acid  which  increases  the  secretion  of 
urine  by  direct  stimulation  of  the  renal  epithelium. 

Chimaphila,  or  pipsissewa,  contains  a  volatile  substance,  Chimaphilin,  and 
arbutin,  and  is  used  as  a  substitute  for  Uva  ursi. 

PREPARATIONS. 

Uva  Ursi  (U.  S.  P.),  Uvae  Ursi  Folia  (B.  P.),  the  leaves  of  Arctostaphylos 
Uva-ursi  (bearberry). 

Fluidextractum  Uvce  Ursi  (U.  S.  P.),  5-15  c.c.  (1-4  fl.  drs.). 

In/mum  Uvce  Ursi  (B.  P.),  i-1  fl.  oz. 

Buchu  (U.  S.  P.),  Buchu  Folia  (B.  P.),  the  leaves  of  Barosma  betulina  and 
B.  crenulata. 

Fluidextractum  Buchu  (U.  S.  P.),  2-4  c,c.  (30-60  mins.), 


78  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

Tinctura  Buchu  (B.  P.),  £-1  fl.  dr. 

Infusum  Buchu  (B.  P.),  1-2  fl.  oz. 

Zea  (U.  S.  P. ),  cornsilk,  the  styles  and  stigmas  of  Zea  Mays  (Indian  corn  or 
maize). 

Extractum  Zece  Fluidum(U.  S.  P.),  5-10  c.c.  (1-2  fl.  drs.). 

Chimaphila  (U.  S.  P.),  Pipsissewa,  the  leaves  of  Chimaphila  umbellata. 

Fluidextractnm  Chimaphilce  (U.  S.  P.),  2-5  c.c.  ($-1  fl.  dr.). 

Fabiana  (Pichi),  the  branches  of  Fabiana  imbricata  (not  pharmacopoaial). 

Fluidextractum  Fabiance,  4  c.c.  (1  fl.  dr.) 

Arbutin  has  been  advised  as  an  improvement  on  the  crude  TJva  ursi.  It 
is  given  in  doses  of  1-4  G. ,  in  sweetened  solution. 

Therapeutic  Uses. — These  drugs  are  all  used  as  mild  disinfectants  of  the 
urinary  tract,  and  are  generally  prescribed  along  with  more  powerful 
diuretics.  They  are  found  to  give  relief  in  catarrh  and  inflammation  of  the 
bladder. 

BIBLIOGRAPHY  OF  UVA  URSI. 

Lewin.     Virchow's  Archiv,  xcii.,p.  521. 
Paschkis.     Wiener  Med.  Presse,  1884,  p.  398. 
Kunkd.     Munch,  med.  Woch.,  1886,  p.  891. 

VI.     SKIN  IRRITANTS  AND  COUNTER-IRRITATION. 

The  practice  of  applying  irritants  to  the  skin  in  internal  diseases  is 
one  of  great  antiquity.  The  theories  on  which  this  therapeutic  method 
is  based  have  changed  with  the  advance  of  medical  knowledge,  until, 
no  explanation  satisfactory  to  modern  scepticism  being  forthcoming, 
the  use  of  these  remedies  has  fallen  into  a  certain  disrepute  in  the 
last  few  years.  The  old  theory  of  revulsion  or  derivation  was  at  first 
based  on  the  belief  that  disease  was  a  malignant  entity  or  humor, 
which  might  be  drawn  from  the  deeper  organs  to  the  surface  by  means 
of  irritation  of  the  skin.  Later,  it  was  supposed  that  the  congestion 
of  the  diseased  organs  might  be  relieved  by  the  withdrawal  of  fluid  to 
the  skin,  and  this  belief  has  been  held  in  more  or  less  modified  forms 
in  quite  modern  times.  In  addition,  it  was  recognized  very  early  that 
irritation  of  the  skin  relieved  pain  in  many  instances.  The  means  by 
which  the  skin  irritation  was  attained,  were  extremely  numerous  and 
varied ;  large  numbers  of  drugs  have  been  used,  and  in  addition  me- 
chanical devices  of  all  kinds  were  employed,  such  as  burning,  electri- 
cal currents,  or  the  introduction  of  setons.  In  many  of  these  the  idea 
of  irritation  was  combined  with  that  of  leaving  a  way  of  escape  for 
humors.  This  latter  is  only  of  historical  interest,  but  the  practice  of 
relieving  internal  organs  by  external  irritation  or  counter-irritation  per- 
sists still,  and  perhaps  merits  more  attention  than  it  receives  at  the 
hands  of  many  physicians. 

The  effects  of  a^n  irritant  applied  jto  the  skin  are  local  and  remote. 
The  first  symptoms  of  irritation  are  congestion  and  redness  of  the 
part,  and  many  drugs  which  produce  only  this  degree  of  irritation  in 
ordinary  circumstances,  are  known  as  Rubefacients.  Stronger  irritants 
cause  blistering,  and  are  called  Vesicants,  while  some  drugs  which 
cause  irritation  and  small  discrete  suppurations,  receive  the  name  of 
Pustulants. 


SKTN  IRRITANTS  AND   COUNTER-IRRITATION.  79 

Local  Symptoms. — The  application  of  an  irritant  to  the  skin  causes 
*a  feeling  of  warmth,  and  often  of  itching,  which  may  later  become 
intensified  into  actual  pain.  The  skin  becomes  red,  congested,  warm, 
and  at  first  is  more  sensitive  to  touch  and  painful  stimuli,  though  the 
sensitiveness  is  afterwards  lessened.  This  condition  persists  for  a 
longer  or  shorter  time  according  to  the  nature  of  the  irritant,  and  then 
passes  off  slowly.  Very  often  desquarnation  follows,  if  the  rubefacient 
has  acted  for  some  length  of  time.  Stronger  irritation  is  followed  at 
first  by  the  same  results,  but  soon  small  globules  of  fluid  appear  below 
the  epidermis,  and  these  coalesce  so  as  to  form  a  large  accumulation 
of  fluid,  which  raises  the  epidermis  completely  off  the  true  skin,  form- 
ing a  blister.  If  the  irritant  be  removed,  the  fluid  of  the  blister  un- 
dergoes a  slow  absorption,  so  that  in  the  course  of  a  few  days  the  epi- 
dermis forms  an  empty  sack,  which,  however,  is  not  obliterated  by  the 
adhesion  of  the  walls.  If  the  blister  be  opened,  the  sensitive  dermis 
is  exposed,  and  the  secretion  of  fluid  continues  for  some  time,  until  a 
new  epidermis  has  been  formed. 

The  distinct  and  separate  points  of  inflammation  caused  by  the 
pustulants  are  due  to  their  affecting  the  orifices  of  the  skin  glands  and 
not  the  intervening  tissue.  This  has  been  ascribed  in  some  instances 
to  the  drug  being  rendered  irritant  at  these  points  by  the  presence  of 
acids  formed  by  the  decomposition  of  the  sebum  and  perspiration  ;  a 
simpler  explanation  is  that  the  pustulants  cannot  pass  through  the 
horny  epidermis,  but  act  as  irritants  wherever  they  come  in  contact 
with  living  tissue,  that  is,  at  the  orifices  of  the  glands.  They  cause 
the  same  sensation  of  warmth  and  prickling  of  the  skin  as  the  other 
irritants,  but  even  in  the  earlier  stages  of  their  action  small,  dark-red, 
raised  points  are  observed,  exactly  as  in  some  of  the  exanthemata,  and 
these  afterwards  form  small  abscesses.  If  the  application  be  persisted 
in,  these  discrete  abscesses  may  burst  through  the  intervening  tissues 
and  become  confluent,  and  large  abscesses  have  thus  been  formed  in 
the  skin.  When  the  irritant  is  removed  before  the  formation  of  pus, 
the  inflammation  of  the  ducts  slowly  subsides  and  the  epidermis  peels 
off  as  after  the  milder  irritants.  Pustulants  are  seldom  employed  at 
the  present  time  ;  croton  oil  applied  vigorously  may  induce  pustula- 
tion,  and  tartar  emetic  was  formerly  largely  used  for  this  purpose. 

The  local  effects  of  the  rubefacients  and  vesicants  are  identical  with 
those  or  acuteTnffammatiori.  The  pain  and  discomfort  are  due  to  the 
'UlHiuil  Oil  IM  iierveTerminations,  while  the  redness  and  swelling  be- 
tray the  local  dilatation  of  the  vessels.  This  latter  is  perhaps  due  to 
the  direct  effect  of  the  irritant  on  the  vessel  walls,  rather  than  to  any 
reflex  action  from  the  irritation  of  the  sensory  nerves,  but  it  cannot  be 
said  to  be  known  how  far  this  latter  agency  is  involved  in  the  result. 
The  dilatation  of  the  vessels  and  the  slowing  of  the  blood  current  in 
them  lead  to  the  transudation  of  fluid  and  leucocytes  into  the  tissues, 
especially  at  the  points  where  the  irritation  is  greatest,  and  the  accu- 
mulation eventually  pushes  off  the  horny  epidermal  layer  from  the 
living  layers  and  forms  a  blister.  The  fluid  in  the  blister  has  been 


80  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

shown  to  contain  some  of  the  irritant,  which  diffuses  into  it  through 
the  epidermis.  The  oedema  and  swelling  is  not  confined  to  the  skin, 
but  extends  into  the  subcutaneous  tissue  and  the  more  superficial  layers 
of  muscle. 

If  the  irritation  be  continued  long  enough,  suppuration  may  com- 
mence in  the  blister  and  lead  to  deep  erosion  of  the  tissues. 

Remote  Action. — Local  irritation  cannot  exist  without  causing  cer- 
tain  general  changes  which  affect  the  whole  organism.  These  arise 
from  the  reflex  stimulation  of  various  centres  in  the  medulla  oblongata, 
and  are  thought  to  explain  many  of  the  beneficial  effects  of  counter- 
irritation.  The  centres  involved  are  those  regulating  the  heart,  the 
.tone  of  the  vessels,  ami  the  respiration.  IVJodefafe  irritation  of  the 
skin"  causes^arT  acceleration  of  the  heart-rhythm,  which  has  not  been 
satisfactorily  explained,  while  more  powerful  irritation  slows  the  heart 
through  the  inhibitory  centre.  The  blood-pressure  measured  in  the 
arteries  is  considerably  increased  by  ordinary  irritation  of  the  skin, 
but  if  it  be  very  severe  or  wi3espread,  the  slowness  of  the  pulse  may 
cause  a  fall  of  tension.  This  increase  in  the  blood-pressure  is  due  to 
tke_LeJ(lex  stimulation  of  the  vasomotor  centre,  which  causes  a  constric- 
tion of  the  arterioles  over  wide  areas  of  the  body; '  The  constriction 
is  not  general,  however,  but  seems  to  affect  the  abdominal  organs 
chiefly,  while  the  vessels  or1  tKe  limbs  and  probably  those  of  the  skin 
are  not  contracted.  The  result  is  that  while  the  blood-pressure  is 
raised  equally  throughout  the  body,  the  resistance  to  the  circulation  is 
greater  in  the  abdominal  organs  than  in  the  rest  of  the  body,  and  more 
blood  is  accordingly  supplied  to  the  muscles  and  skin  and  less  to  the 
internal  organs  than  normally. 

The  effects  of  skin  irritation  on  the  respiration  are  less  uniform.  In 
the  rabbit  the  breathing  is  sometimes  accelerated,  sometimes  slowed  by 
mild  stimulation,  while  stronger  stimuli  seem  to  slow  it  always.  The 
effect  of  the  application  of  skin  irritants  on  the  respiration  in  man  has 
not  been  observed  accurately,  but  that  sudden  stimulation  of  the  skin 
causes  gasping  and  irregularity  of  the  respiration,  may  be  observed 
whenever  cold  water  comes  in  contact  with  the  more  sensitive  parts  of 
the  body. 

The  temperature  of  the  body  also  undergoes  changes  when  the  skin 
is  irritated.  When  the  irritation  is  slight,  an  increase  in  the  rectal 
temperature  is  often  observed  at  first,  while  a  decrease  follows  later, 
but  on  powerful  stimulation,  the  preliminary  rise  of  temperature  is  so 
short  as  to  escape  observation  by  ordinary  methods,  while  the  subse- 
quent fall  is  more  distinct  and  prolonged.  The  skin  temperature  is 
raised  at  the  same  time  as  the  internal  temperature  falls.  The  expla- 
nation of  these  changes  in  the  internal  and  external  temperatures  is 
obviously  the  altered  distribution  of  the  blood,  more  of  which 
flows  through  the  skin  vessels  and  is  cooled  than  usual.  This  results 
in  a  fall  of  the  internal  temperature  and  a  rise  in  that  of  the  skin, 
through  the  warm  blood  from  the  interior  of  the  body  pouring  through 


SKIN  IRRITANTS  AND   COUNTER-IRRITATION.  81 

the  superficial  vessels.  The  preliminary  rise  in  the  temperature  has 
not  been  explained.  The  whole  subject  of  the  alteration  of  the  tem- 
perature through  counter-irritation  has  perhaps  received  greater  atten- 
tion than  it  deserves,  if  the  observations  of  Jacobson  be  correct,  for 
he  found  the  variations  in  man  to  amount  to  less  than  one-tenth  of  a 
degree  Centigrade  as  a  general  rule. 

The  metabolism  has  been  found  to  be  altered  by  the  application  of 
irritanf sTo  tlfe  "skin,  and,  although  in  the  experiments  on  which  this 
statement  is  based,  the  surface  exposed  to  the  irritant  was  larger  than 
that  affected  in  therapeutics,  it  seems  probable  that  some  change  is  pro- 
duced by  the  ordinary  agents  also.  Zuntz  and  Rohrig  found  that  bath- 
ing animals  in  strong  salt  solution  increased  the  oxygen  absorbed  and 
the  carbonic  acid  excreted  much  more  than  bathing  in  ordinary  water, 
and  Paalzow  obtained  the  same  result  from  the  application  of  mustard 
plaster.  The  nitrogen  of  the  urine  is  also  said  to  be  increased.  This 
increase  in  the  oxidation  of  the  tissues  is  of  the  same  nature  as  that  pro- 
duced by  cold,  and  is  due  to  an  augmentation  of  the  muscular  activity, 
which,  however,  is  too  slight  to  cause  any  perceptible  movement. 

Jmtationjof  Jthe ;  skin  induces  leucocytosis  in  the  same  way  as  irrita- 
tion of  the  alimentary  canal.  This  is  especially  evident  after  the 
application  of  a  vesicant  such  as  cantharides  plaster,  while  rubefaction 
seems  to  have  less  effect.  The  injection  of  irritants  into  the  subcutane- 
ous tissues  induces  a  leucocytosis  similar  to  that  following  can- 
tharides. 

Lastly,  in  considering  the  effects  of  skin  irritation  on  the  general 
vitality,  it  may  be  mentioned  that  a  sudden  application  may  awake  the 
consciousness,  as  is  seen  in  the  effects  of  dashing  cold  water  on  the 
cEest,  or  of  striking  the  hands  in  narcotic  poisoning.  Another  example 
is  seen  in  the  improved  mental  condition  so  often  observed  in  fever 
patients  treated  with  cold  baths.  This  improvement  is  due  to  the 
changes  in  the  skin,  and  not,  as  is  often  said,  to  the  fall  in  temperature, 
for  the  latter  is  often  insignificant. 

All  of  these  effects  are  produced  by  irritation  at  any  point  of  the 
surface,  and  are  quite  insufficient  to  explain  the  practical  use  of  counter- 
irritants  to  affect  a  particular  organ.  For  example,  in  gastric  disor- 
ders a  counter-irritant  is  often  applied  just  over  the  ensiform  cartilage, 
while  in  facial  neuralgia  a  blister  behind  the  ear  often  gives  relief.  If 
the  beneficial  results  were  due  to  the  general  alteration  of  the  circula- 
tion, respiration,  or  temperature,  there  would  be  no  reason  to  vary  the 
point  of  application,  for  the  effect  would  not  vary.  Zuelzer,  there- 
fore, attempted  to  ascertain  whether  the  deeper  tissues  and  the  internal 
organs  were  affected  by  superficial  irritation  over  them,  and  found 
that  when  cantharides  was  applied  to  one  side  of  a  rabbit's  back 
for  fourteen  days,  the  superficial  muscles  under  it  were  congested, 
while  the  deeper  layers  and  the  lung  were  anaemic  when  compared 
with  the  corresponding  parts  on  the  other  side.  His  treatment,  how- 
ever, led  to  necrosis  and  suppuration,  so  that  his  conclusions  are  not 
unimpeachable.  Lazarus-Barlow  and  Philipps  observed  recently  that 


82  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

the  muscles  on  the  same  side  as,  but  at  some  distance  from  a  blister, 
were  of  higher  specific  gravity  than  those  on  the  uninjured  side,  while 
those  immediately  below  the  blister  were  of  lower  specific  gravity,  and 
therefore  concluded  that  fluid  was  drawn  from  the  deeper  muscles  to 
supply  the  superficial  ones.  This,  however,  evidently  requires  that 
the  internal  organs  to  be  affected  must  be  not  only  contiguous,  but 
also  continuous  with  those  directly  aifected,  and  offers  no  explanation 
of  the  alleged  effects  of  irritation  of  the  skin  upon  the  stomach  or 
lungs.  Much  light  has  been  thrown  on  the  subject  by  the  researches 
of  Head,  who  found  that  in  many  cases  internal  disease  is  accom- 
panied by  a  tenderness  of  the  skin,  and  mapped  out  with  care  the  skin 
areas  corresponding  to  each  organ.  In  this  way  he  was  able  to  show 
that  a  distinct  relation  exists  between  irritation  of  an  internal  organ 
and  that  part  of  the  skin  which  is  supplied  l>y  the  same  segment;  of 
tnTspin'al "cord  or  brain.  Thus  in  painful  diseases  of  the  stomach,  ten- 
derness is  often  complained  of  in  the  skin  of  the  epigastrium,  while  in 
oesophageal  stricture,  pain  is  often  referred  to  a  point  near  the  angle  of 
the  scapula  and  to  another  in  the  neighborhood  of  the  apex-beat. 
The  superficial  points  are,  of  course,  only  connected  with  the  diseased 
organ  by  means  of  nerve-fibres,  but  Head's  observations  show  that  a 
nervous  impulse  from  these  organs  does  not  pass  in  an  indeterminate 
manner  through  the  central  nervous  system,  but  has  a  distinct  tendency 
to  affect  the  superficial  areas  which  are  supplied  with  sensory  nerves 
from  the  same  segment  of  the  cord.  It  would,  therefore,  seem  a  plaus- 
ible theory  that  an  affection  of  these  superficial  areas  may  affect  the 
corresponding  internal  organ  more  than  the  rest  of  the  body,  and  this 
is  exactly  what  is  required  to  explain  the  benefits  derived  from  the  use 
of  counter-irritants.  It  is  especially  noticeable  that  several  of  the 
points  which  Head  observed  to  be  affected  by  internal  disease  are 
precisely  those  points  at  which  experience  has  shown  irritation  to 
be  most  beneficial.  (Fig.  1.)  Thus  the  application  of  a  blister  over 
the  epigastrium  has  long  been  recognized  as  a  means  of  relieving  gas- 
tric disorders.  Similarly  the  old  treatment  of  iritis  by  means  of  a 
blister  on  the  temple  may  be  justified  by  the  fact  that  Head  found 
areas  of  tenderness  on  the  temple  accompanying  this  disease. 

The  exact  nature  of  the  effects  of  counter-irritation  on  the  internal 
organs  has  not  been  ascertained,  but  it  would  seem  most  probable  that 
an  alteration  in  the  calibre  of  the  vessels  and  in  thej^sory  nerves «or 
their  terminations  is  induced.  These  alterations  may,  however,  pro- 
duce or  be  accompanied  by  a  distinct  alteration  in  the  activity  of  the 
organs ;  for  example,  there  seems  good  reason  to  believe  that  in  many 
cases  irritants  applied  to  the  abdomen  produce  evacuation  of  the  bowels. 

Besides  these  physiological  effects  of  counter-irritation,  it  must  not 
be  forgotten  that  a  great  impression  is  produced  on  the  patient,  and 
that  some  of  the  benefit  may  be  due  to  hypnotic  suggestion. 

Therapeutic  Uses.— Local  irritants  are"  applied  occasionally  to  pro- 
duce an  alteration  in  the  nutrition  and  blood  supply  of  the  skin  itself 
and  of  the  subcutaneous  tissues.  Thus  in  some  chronic  inflammatory 


SKIN  IRRITANTS  AND   COUNTER-IRRITATION.  83 

conditions,  with  effusions  into,  or  indurations  of  the  subcutaneous  tis- 
sues, the  improvement  of  the  circulation  produced  by  slight  irritation 


FIG.  1. 


The  right  side  is  divided  into  segments  which  correspond  to  some  of  the  skin  areas  in  which  Head 
found  tenderness  in  internal  diseases.  1.  Area  of  tenderness  in  disease  of  the  lungs.  2.  In  diseases 
of  the  stomach.  3.  In  ovarian  disease.  4.  In  disease  of  the  Fallopian  tubes  and  other  appendages. 
On  the  left  side  are  represented  the  points  of  application  of  counter-irritants  in  disease  of  the  lungs 
(A),  of  the  stomach  (B),  of  the  ovary  (C),  and  of  the  uterine  appendages  (Z>). 

may  be  of  benefit.  An  example  of  this  is  the  treatment  of  ulcers  of 
old  standing  with  irritants.  Another  case  in  which  a  slight  inflamma- 
tory attack  causes  very  obvious  improvement,  is  in  corneal  opacity, 
which  may  be  removed  entirely  in  some  cases  by  the  acute  inflam- 
matory reaction  produced  by  such  irritants  as  abrin.  Probably  a 
similar  effect  is  produced  on  subcutaneous  effusions,  as  in  bruises. 
Some  interesting  experiments  on  this  subject  have  recently  been  per- 
formed by  Wechsberg,  who  induced  suppuration  in  both  hind  legs  of 
rabbits  by  the  injection  of  irritants  and  then  treated  the  one  leg  by  the 
application  of  various  irritants  to  the  skin,  while  the  other  was  left 
untreated  as  a  control.  He  invariably  found  the  abscess  of  the  leg 
subjected  to  treatment  less  extensive  and  showing  a  greater  tendency 
to  heal  than  the  other,  and  accounts  for  this  by  the  oedema  induced  by 
the  skin  irritant  diluting  the  original  irritant  and  promoting  its 
absorption.  The  increased  blood  supply  leads  to  a  larger  number  of 
leucocytes  and  more  alexines  around  the  inflammation  than  would 
otherwise  be  present.  He  found  that  the  absorption  of  pigments  from 


84  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

the  rabbit's  ear  was  much  accelerated  by  the  application  of  irritants  to 
the  skin  over  the  part,  and  cites  this  as  evidence  that  toxines  are 
removed  more  rapidly  under  similar  treatment.  For  these  purposes 
only  the  milder  irritants  are  required  ;  in  fact,  vesication  may  do  more 
harm  than  good.  Mild  irritation  alters  the  sensitiveness  of  the  sen- 
sory organs  of  the  skin,  and  heat  is  often  applied  to  alleviate  pain  and 
discomfort  in  the  skin  itself.  In  other  instances  pain  is  increased  by 
heat,  and,  in  fact,  it  is  sometimes  applied  in  the  treatment  of  local 
anaesthesia,  with  the  object  of  rendering  the  surface  more  sensitive. 
In  many  forms  of  skin  disease,  mild  irritants  are  found  to  be  of  bene- 
fit ;  this  is  sometimes  attributed  to  their  antiseptic  action,  but  the 
slight  irritation  is  undoubtedly  of  some  importance. 

Counter-irritants  are  used  in  a  large  number  of  diseases,  often  with- 
out any  definite  idea  of  what  precise  effects  they  will  elicit,  but  merely 
because  they  have  been  found  to  give  relief  in  similar  conditions.  As  a 
general  rule  they  are  placed  over  the  affected  organ,  and  this  corre- 
sponds fairly  in  most  cases  of  disease  of  the  trunk  with  Head's  area  of 
skin  tenderness.  In  the  head,  however,  the  segmental  arrangement 
has  been  rendered  very  irregular  by  the  compression  in  development, 
and  counter-irritants  are  often  found  to  be  most  effective  when  placed 
at  some  distance  from  the  seat  of  pain,  e.  #.,  behind  the  ear  in  some 
forms  of  facial  neuralgia.  They  are  used  in  acute  inflammation  of  the 
lungs  and  pleura,  in  gastric  disorders  accompanied  by  much  pain,  in 
colic  and  in  neuralgia  and  neuritis.  Their  action  is  very  uncertain,  but 
their  application  is  often  followed  by  great  relief,  more  especially  of 
pain.  They  are  also  used  occasionally  in  shock  or  collapse,  not  for 
their  effect  on  any  individual  organ,  but  to  elicit  the  reflex  alterations 
in  the  circulation  which  have  already  been  described.  A  blister  is 
often  recommended  in  internal  haemorrhage,  and  may  very  possibly 
lessen  the  bleeding  by  altering  the  distribution  of  the  blood  in  the 
organs,  although  it  is  difficult  to  estimate  how  far  the  improvement  is 
due  to  the  remedy  and  how  far  it  is  spontaneous.  In  order  to  produce 
any  marked  effect  on  internal  organs,  the  more  powerful  irritants  must 
be  used,  such  as  mustard  or  cantharides.  It  is  not  necessary,  however, 
to  produce  actual  vesication  in  the  great  majority  of  cases.  Formerly 
blisters  were  opened  and  fresh  irritants  applied  on  the  raw  surface  in 
order  to  prolong  the  effects,  but  this  treatment  was  extremely  painful, 
besides  being  liable  to  set  up  suppuration  and  ulceration,  and  it  is 
very  questionable  whether  any  equivalent  benefit  followed. 

Counter-irritation  must  be  applied  only  with  the  greatest  caution  in 
weak,  badly  nourished,  or  very  old  persons,  as  it  may  cause  sloughing. 
In  diabetes,  the  tendency  to  gangrene  contraindicates  blistering,  and 
in  very  young  children  only  mild  irritants  are  used. 

BIBLIOGRAPHY. 

Naumann.     Vierteljahrsch.  f.  prakt.  Heilkunde,  Ixxvii.,  p.  1,  and  xciii.,  p.  133. 
Ziilzer.     Deutsche  Klinik.,  1865,  p.  127. 


Rohrig.     Ibid.,  1873,  p.  209. 
fliiger' 
Paalzow.     Ibid.,  iv.,  p.  492. 


Rohrig  and  Zuntz.     Pfliiger's  Arch.?  iy.,  p.  57. 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION.  85 

Wertkeimer.     Arch,  de  Phys.,  1894,  pp.  308  and  724. 

Hddenhain.     Pfliiger's  Arch.,  iii.,  p.  504;  v.,  p.  77. 

Riegel.     Ibid.,  iv.,  p.  350. 

Mantegazza.     Schmidt's  Jahrb.,  cxxxiii.,  p.  153. 

Jacobson.     Virchow's  Arch.,  Ixvii.,  p.  166. 

Head.     Brain,  xvi.,  p.  1 ;  xvii.,  p.  339. 

Schuller.     Berl.  klin.  Woch.,  1874,  p.  294. 

Winternitz.     Arch.  f.  exp.  Path,  und  Pharm.,  xxxv.,  p.  77  ;  xxxvi.,  p.  212. 

Wesseley.     Centralbl.  f.  Chirur.,  xxx.,  No.  36. 

Hay.     Saline  Cathartics,  pp.  128-144. 

Buthner,  Fuchs,  Megele.     Arch.  f.  Hygiene,  xl.,  p.  347. 

Wechsberg.     Ztschr.  f.  klin.  Med.,  xxxvii.,  p.  360. 

An  enormous  number  of  drugs  produce  irritation  of  the  skin,  and 
it  would  be  idle  to  attempt  to  enumerate  them  here.  In  many  in- 
stances, however,  the  irritant  action  is  insignificant  in  comparison  with 
the  other  effects  produced,  and  these  will,  therefore,  be  discussed  else- 
where; among  these  are  found  some  of  the  alkaloids,  the  acids  and 
alkalies,  and  many  other  inorganic  preparations.  Irritation  of  the  skin 
may  also  be  produced  by  heat  and  cold,  and  in  fact  burning  in  various 
forms  was  formerly  used  as  a  means  of  counter-irritation.  Heat  is 
still  employed  to  cause  irritation  of  the  skin  and  subcutaneous  tissues, 
and  to  promote  their  circulation.  Thus,  poultices  and  hot  water  com- 
presses are  beneficial  in  many  local  inflammations,  though  the  same 
effects  may  generally  be  obtained  by  the  use  of  the  milder  irritants. 
The  effect  of  cold  on  the  skin  is  more  frequently  demonstrated  by 
bathing,  and  will  be  touched  on  in  relation  to  the  antipyrine  series. 

Apart  from  those  drugs  in  which  the  irritation  of  the  skin  is  merely 
an  incident  in  a  wider  general  action,  there  are  a  number  of  prepara- 
tions which  are  used  almost  exclusively  for  this  purpose.  They  may 
be  divided  into  three  classes :  the  volatile  irritants,  such  as  turpentine 
oil;  the  mustard  series,  some  of  which  are  also  volatile;  and  those 
which  are  either  non-volatile  or  only  boil  at  high  temperatures,  such 
as  cantharidin. 

I.   The  Turpentine  Oil  Group. 

Under  the  volatile  irritants  may  be  included  a  large  number  of  the 
ethereal  oils  and  many  members  of  the  methane  and  of  the  aromatic 
series;  but  among  the  ethereal  oils  those  which  possess  a  low  boiling 
point,  that  is,  those  which  contain  a  large  proportion  of  terpene,  with 
comparatively  little  oxygen,  are  found  to  possess  a  more  penetrating 
action  than  the  others.  At  the  same  time,  the  taste  and  odor  of  these 
oils  is  often  less  pleasant  than  that  of  the  others,  so  that  they  are  less 
used  as  flavors  and  carminatives.  The  oils  derived  from  the  Coni- 
ferse  have,  for  this  reason,  been  more  largely  used  than  the  others  for 
their  effect  on  the  skin,  although  several  other  volatile  preparations  are 
recognized  by  the  pharmacopoeia  for  this  purpose.  The  action  of  these 
oils  is  similar  in  other  respects  to  that  of  the  general  group  (see  p.  61), 
so  that  it  need  not  be  discussed  here. 

PKEPA  RATIONS. 

Terebinthina,  turpentine  (U.  S.  P.),  Thus  Americanum,  Frankincense 
(B.  P.),  a  concrete  oleoresin  obtained  from  Pinus  palustris  and  other  species 
of  Pinus. 


86  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

Terebinthina  Canadensis  (U.  S.  P.,  B.  P.),  Canada  balsam,  a  liquid  oleo- 
resin  obtained  from  Abies  balsamea. 

Fix  Burgundica,  Burgundy  Pitch  (B.  P.),  an  oleoresin  derived  from  Abies 
excelsa,  Norway  spruce  fir,  contains  less  volatile  oil  than  turpentine. 

OLEUM  TEREBINTHINA  (U.  S.  P.,  B.  P.),  oil  of  turpentine,  a  volatile  oil 
distilled  from  turpentine. 

Oleum  Terebinthince  Rectification  (U.  S.  P.),  is  formed  from  ordinary  oil  of 
turpentine  by  redistillation  with  lime  water,  in  order  to  remove  any  acids  and 
resin  which  may  be  contained  in  it.  It  consists  of  a  mixture  of  terpenes 
(C10H16).  Dose,  1  c.c.  (15  mins.);  as  an  anthelmintic,  8-15  c.c.  (2-4  fl.  drs.). 

Emulsum  Old  Terebinthince  (U.  S.  P.),  4  c.c.  (1  fl.  dr.). 

Linimentum  Terebinthince  (U.  S.  P.,  B.  P.). 

Linimentum  Terebinthince  Aceticum  (B.  P.),  is  formed  by  mixing  turpentine, 
glacial  acetic  acid  and  camphor  liniment. 

Emplastrum  Picis  (B.  P.),  pitch  plaster. 

Oleum  Pini  (B.  P.),  the  oil  distilled  from  the  fresh  leaves  of  Pinus  pumilis. 

Terebenum  (U.  S.  P.,  B.  P.),  a  liquid  formed  from  oil  of  turpentine  by  the 
action  of  sulphuric  acid.  It  consists  of  a  number  of  terpenes,  one  of  which 
is  the  pure  substance  known  as  terebene.  Its  odor  is  more  pleasant  than 
that  of  turpentine  oil,  which  it  closely  resembles  in  most  other  points. 

Terpini  Hydras  (U.  S.  P.),  terpin  hydrate,  is  a  crystalline  substance 
(C}0H16(OH)2  +  H2O)  derived  from  oil  of  turpentine  by  the  action  of  nitric 
acid  in  the  presence  of  alcohol  and  water.  It  possesses  almost  no  odor,  is 
insoluble  in  water,  and  melts  at  about  116°  C. 

Sabina  (U.  S.  P.),  the  tops  of  Juniperus  sabina,  savine,  contains  as  its  ac- 
tive principle  Ol.  Sabinse,  a  volatile  oil  which  resembles  that  of  turpentine 
in  many  respects,  but  is  not  identical  with  it. 

Oleum  Juniper!  (U.  S.  P.,  B.  P.),  oil  of  Juniper,  is  derived  from  the  jum- 
per berries  and  consists  mainly  of  terpenes.  Dose,  0.03-0.2  c.c.  (£-3  mins.). 

Spiritus  Juniperi  (U.  S.  P.,  B.  P.),  1-4  c.c.  (15-60  mins.). 

Spiritus  Juniperi  Compositus  (U.  S.  P.),  4-8  c.c.  (1-2  fl.  drs.). 

In  addition  to  these  preparations  the  following  may  be  mentioned  here  as 
possessing  similar  action  and  uses. 

Linimentum  Chloroformi  (U.  S.  P.,  B.  P.). 

Linimentum  Camphorse  (U.  S.  P.,  B.  P.). 

Linimentum  Camphorse.  Ammoniatum  (B.  P.). 

Linimentum  Saponis  (U.  S.  P.,  B.  P.),  very  slightly  irritant. 

Emplastrum  Arnicse  (U.  S.  P.). 

Ceratum  Camphorss  (U.  S.  P.). 

Therapeutic  Uses. — Turpentine  oil  is  used  externally  as  a  rubefacient, 
and  differs  from  mustard  and  cantharidin  in  its  greater  penetrating 
power.  It  is  not  so  irritant,  however;  it  blisters  only  after  long  appli- 
cation, and  the  vesication  produced  is  very  painful  and  heals  slowly, 
from  the  vapor  penetrating  into  the  deeper  tissues.  It  is,  therefore, 
employed  to  produce  rubefaction  only,  and  ought  to  be  removed  when 
this  is  attained.  For  this  purpose  any  of  the  liniments  of  the  group 
may  be  employed,  or  a  more  intense  action  may  be  got  from  the  "  tur- 
pentine stupe,"  which  is  made  by  dipping  flannel  in  hot  water,  wringing 
it  dry,  and  then  dropping  warm  turpentine  oil  on  it.1  Turpentine 
preparations  are  used  especially  in  rheumatic  affections  of  the  joints  or 
muscles,  and  in  sciatica.  The  oleoresins  may  be  formed  into  ointments, 

1  Alcohol  has  recently  been  applied  in  a  similar  way  in  phlegmon  and  other  forms  of 
inflammation.  Gauze  is  soaked  in  alcohol  (60-96  per  cent. ),  wrung  out,  wound  round 
the  affected  part  and  covered  with  cotton  and  oil-cloth. 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION.  87 

or  plasters,  and  used  as  feeble  stimulants  in  skin  diseases.  Turpen- 
tine oil  is  a  fairly  strong  antiseptic,  and  is  less  irritant  than  many  of 
the  more  powerful  ones.  It  is  often  inhaled  in  lung  diseases  such  as 
tuberculosis  or  gangrene,  and  has  the  effect  of  lessening  the  odor  in 
the  latter;  the  oil  may  be  simply  allowed  to  evaporate,  but  is  much 
more  efficient  when  sprayed  into  the  air.  Many  of  the  resorts  for 
phthisical  patients  are  stated  to  be  rendered  especially  suitable  for  the 
treatment  of  this  disease  by  the  neighborhood  of  coniferous  forests, 
which  are  supposed  to  dissipate  the  oils  into  the  atmosphere ;  but  this 
is  probably  only  an  insignificant  factor  in  the  treatment.  Turpentine 
oil  is  occasionally  added  to  baths  in  order  to  cause  a  slight  general 
stimulation  of  the  skin,  which  may  be  of  benefit  in  some  skin  diseases 
and  also  in  general  debility  under  certain  conditions ;  and  pine-needle 
baths  have  some  reputation  in  Germany  for  the  same  reason,  the  water 
being  supposed  to  extract  the  oil. 

Internally,  turpentine  oil  is  occasionally  employed  as  a  vermifuge, 
but  is  inferior  to  other  preparations  used  for  this  purpose.  A  few  drops 
are  often  added  to  purgative  enemata  to  increase  their  efficiency.  It  has 
been  given  by  the  mouth  in  order  to  lessen  flatulence  and  to  disinfect 
the  intestine  in  various  diseases,  among  others,  typhoid  fever,  although 
its  value  here  is  disputed.  Preparations  of  turpentine  oil  and  juniper 
are  reliable  and  fairly  powerful  diuretics,  but  must  not  be  prescribed 
in  irritation  of  the  kidney.  The  turpentine  preparations  have  a  cer- 
tain reputation  as  expectorants,  and  terebene  has  been  especially  ad- 
vised for  this  purpose ;  they  are  also  given  internally  as  pulmonary 
disinfectants.  In  some  forms  of  neuralgia  their  internal  administration 
has  been  found  beneficial,  and  oil  of  turpentine  has  been  used  in 
internal  hemorrhage,  but  with  doubtful  results.  Old  oil  of  turpentine 
was  formerly  advocated  in  phosphorus  poisoning,  but  this  treatment 
has  proved  to  be  valueless. 

Along  with  these  may  be  mentioned  a  series  of  resins  which  have  some  slight 
irritating  effect  on  the  skin,  and  have  been  used  in  the  treatment  of  skin  dis- 
eases. 

Resina  (U.  S.  P.,  B.  P.),  resin,  colophony,  is  the  residue  left  after  distilling 
off  the  volatile  oil  from  turpentine. 

Ceratum  Reduce  (U.  S.  P. ). 

Ceratum  Resince  Compositum  (U.  S.  P.). 

Emplastrum  Resince  HJ.  S.  P.,  B.  P.),  adhesive  plaster. 

Unguentum  Resince  (B.  P.). 

Galbanum  (B.  P.),  a  gumresin  obtained  from  Ferula  galbaniflua  and  prob- 
ably from  other  species.  It  contains  some  volatile  oil,  gums  and  resin.  Dose, 
5-15  grs. 

Pilula  Galbani  Composita  (see  Asafcetida). 

Ammoniacum  (B.  P.),  a  gumresin  obtained  from  Dorema  Ammoniacum,  and 
containing  a  small  quantity  of  a  volatile  oil  with  an  unpleasant  odor. 

Emplastrum  Ammoniaci  cum  Hydrargyri  (B.  P.). 

Mistura  Ammoniaci  (B.  P.),  £-1  fl.  oz. 

Guaiaci  Lignum  (B.  P.),  the  heart- wood  of  Guaiacum  officinale. 

Guaiacum  (U.  S.  P.),  Guaiaci  Resina  (B.  P.),  the  resin  obtained  from  Guaia- 
cum officinale,  contains  several  resinous  acids,  some  volatile  oils  and  gums.  It 
is  colored  deep  blue  by  oxidizing  agents. 


88  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

Tinctura  Guaiaci  (U.  S.  P.),  4  c.c.  (1  fl.  dr.). 

Tinctura  Guaiaci  Ammoniata  (U.  S.  P.,  B.  P.),  2-4  c.c.  (£-1  fl.  dr.). 

Mistura  Guaiaci  (B.  P.),  £-1  fl.  oz. 

Trochiscus  Guaiaci  Resinse  (B.  P.),    each  containing  3  grs. 

Elemi  resin  (not  official)  is  obtained  from  a  number  of  trees  of  the  order 
Burseracea?,  and  contains  volatile  oil  and  resins. 

Unguentum  Elemi  (not  official). 

Myrrha  (U.  S.  P.,  B.  P.),  a  gumresin  obtained  from  Commiphora  Myrrha 
(U.  S.  P.),  from  Balsamodendron  Myrrha  (B.  P.),  containing  a  small  quantity 
of  volatile  oil. 

Tinctura  Myrrhse  (U.  S.  P.,  B.  P.),  2-4  c.c.  (\-l  fl.  dr.). 

Pilultz  Aloes  et  Myrrhx  (U.  S.  P.,  B.  P.). 

Tinctura  Aloes  et  Myrrhse  (U.  S.  P.). 

Mistura  Ferri  Composita  (U.  S.  P.). 

Many  other  resins  have  been  used  in  therapeutics,  but  have  been  aban- 
boned,  a  fate  by  which  these  survivors  seem  to  be  threatened.  They  are 
occasionally  used  externally  as  mild  irritant  applications  in  skin  affections. 
Galbanum,  Ammoniacum,  Guaiacum  and  Myrrh  have  been  used  internally 
for  many  different  purposes,  as  expectorants,  diaphoretics,  diuretics,  aperi- 
ents, and  have  enjoyed  a  reputation  in  the  treatment  of  amenorrhcea.  They 
may  be  used  to  suspend  insoluble  bodies,  as  the  gum  contained  causes  them 
to  form  emulsions  when  water  is  added. 

II.  Mustard. 

Mustard  occurs  in  two  forms  in  the  pharmacopoeias,  Black  Mustard, 
Sinapis  nigra,  and  White  Mustard,  Sinapis  alba.  Black  Mustard  con- 
tains a  glucoside,  Potassium  Myronate  or  Sinigrin,  and  a  ferment, 
Mi/rosin,  which  decomposes  it  in  the  presence  of  water  into  dextrose, 
potassium  bisulphate  and  allyl-isosulphocyanate  or  volatile  oil  of 
mustard. 

Sinigrin.  Volatile  oil. 

C10H18KNS2010  =  CSNC3H5  +  C6H12O6  +  KHSO4 

Volatile  oil  of  mustard  is  formed  in  various  other  Cruciferae  when  they  are 
mixed  with  water.  Thus  horseradish  root  (Armoracia,  B.  P.)  contains  it, 
while  the  allied  species  Cochlearia  officinalis  apparently  contains  the  corre- 
sponding isobutyl  compound. 

White  mustard  contains  another  glucoside,  Sincdbin,  which  is  also 
decomposed  by  the  Myrosin  in  the  presence  of  water.  The  products 
are  entirely  different,  however,  dextrose,  sulphate  of  sinapine  (an  alka- 
loid), and  an  oil  of  mustard  containing  an  aromatic  nucleus  being 
formed. 

Sinalbin.  Oil  of  Mustard.  Sinapine  Sulphate. 

2S2016  =  C6H4(OH)CH2NCS  +  C16H23NO5H2SO4  +  C6H12O6 


The  oil  of  white  mustard  differs  from  that  of  the  black  in  being  less 
irritant,  and  in  being  destroyed  by  heat. 

Action.  —  Either  of  these  oils  is  intensely  irritant  when  applied  to 
the  skin,  and  if  left  long  enough  produces  blistering,  which  is  more 
painful  than  that  caused  by  cantharides,  and  is  said  to  heal  less  readily. 
This  is  probably  due  to  the  oils  penetrating  more  deeply  into  the  tissues, 
and  thus  setting  up  more  extensive  inflammation.  Mustard  is  accord- 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION.  89 

ingly  used  only  to  induce  rubefaction,  and  ought  to  be  removed  before 
actual  vesication  occurs.  When  the  crude  drug  is  moistened  and  ap- 
plied to  the  skin,  the  oil  is  formed  only  slowly,  so  that  the  longer  it 
remains  applied,  the  more  intense  is  the  action.  The  glucosides  in 
themselves  have  little  or  no  action,  and  the  products  of  their  decom- 
position are  harmless,  with  the  exception  of  the  oils. 

PREPARATIONS. 

Sinapis  Alba  (IT.  S.  P.),  Sinapis  Albae  Semina  (B.  P.),  the  dried  ripe  seeds 
of  Brassica  alba. 

Sinapis  Nigra  (U.  S.  P.),  Sinapis  Nigrse  Semina  (B.  P.),  the  dried  ripe 
seeds  of  Brassica  nigra. 

Sinapis  (B.  P.),  a  mixture  of  the  powdered  seeds. 

CHARTA  SINAPIS  (U.  S.  P.,  B.  P.),  mustard  powder  rendered  adhesive  by 
India-rubber,  applied  to  sheets  of  paper  and  dried.  The  U.  S.  P.  prepara- 
tion is  formed  from  the  black  mustard,  the  B.  P.  from  a  mixture  of  the  two. 

Oleum  Sinapis  Volatile  (U.  S.  P.,  B.  P.),  derived  from  black  mustard. 

Linimentum  Sinapis  (B.  P.),  formed  from  volatile  oil  of  mustard,  camphor 
and  castor  oil. 

Uses. — Mustard  is  largely  used  as  a  condiment  and  to  promote 
appetite,  but  is  never  prescribed  for  this  purpose.  In  large  quantities 
it  causes  violent  irritation  of  the  stomach  and  bowel,  with  vomiting, 
purging,  acute  pain  and  tenderness  in  the  abdomen,  and  collapse. 
Mustard  and  warm  water  is  a  convenient  emetic  in  emergencies,  as  in 
cases  of  poisoning. 

The  plaster  or  leaf  (charta)  is  the  form  in  which  it  is  generally  used 
in  therapeutics.  It  contains  the  glucoside,  which  is  slowly  decomposed 
by  the  ferment  when  the  plaster  is  dipped  in  warm  water  for  a  few  min- 
utes before  application.  Another  popular  application  is  the  mustard 
poultice,  in  which  powdered  mustard  is  sprinkled  on  an  ordinary 
poultice.  Mustard  is  also  added  to  baths  occasionally  when  slight 
irritation  and  consequent  congestion  is  desired  over  a  large  surface. 
For  this  purpose  2—4  teaspoonfuls  of  the  dry  powder  are  added  for 
each  gallon  of  water.  In  preparations  of  mustard  it  is  important  to 
avoid  a  temperature  of  over  60°  C.  (140°  F.),  as  the  ferment  is  de- 
stroyed above  this.  The  plaster  is  left  on  the  skin  only  for  15  to  30 
minutes,  when  it  is  used  as  a  rubefacient. 

III.   Cantharidin  Series. 

Another  series  of  local  irritants  comprises  n on- volatile  substances, 
of  which  cantharidin  is  the  best  known.  It  is  the  anhydride  of  can- 
tharidic  acid,  which  does  not  exist  itself,  but  the  salts  of  which  are 
formed  from  cantharidin  by  the  action  of  bases.  Cantharidin  is  rep- 
resented by  C10H12O4,  and  is  a  derivative  of  benzol.  Its  action  on 
the  central  nervous  system  resembles,  it  is  stated,  that  of  the  other 
members  of  that  series,  but  is  of  no  importance  in  comparison  with 
its  local  irritant  effects.  Cantharidin  is  found  in  Spanish  fly  (Can- 
tharis  vesicatoria,  or  Lytta  vesicatoria)  and  in  several  allied  species  of 
Coleoptera  (beetles).  The  irritant  action  of  cantharidin  and  of  many 


90  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

other  drugs  was  formerly  supposed  to  be  due  to  its  being  an  anhy- 
dride, but  other  anhydrides  have  no  such  specific  action,  and  the  can- 
tharidates  are  quite  as  powerful  as  cantharidin. 

Action. — Applied  to  the  skin,  cantharidin  produces  redness,  smarting 
and  pain,  followed  very  soon  by  small  vesicles,  which  later  coalesce 
into  one  large  blister.  This  is  much  less  painful  than  the  vesication 
produced  by  mustard,  because  less  of  the  irritant  penetrates  into  the 
deeper  tissues  than  in  the  case  of  the  volatile  mustard  oil.  If  the 
blister  be  broken,  however,  and  the  unprotected  dermis  be  allowed  to 
come  in  contact  with  the  irritant,  violent  inflammation  with  much 
pain,  suppuration  and  even  sloughing  may  follow. 

When  large  quantities  of  cantharidin  are  given  internally,  the  same 
irritant  action  takes  place  along  the  alimentary  tract.  If  taken  in 
solution,  blisters  arise  in  the  mouth  and  throat,  and  the  pain  and 
swelling  in  the  oesophagus  may  be  so  acute  as  to  prevent  swallowing. 
The  irritation  of  the  stomach  produces  vomiting,  followed  by  purging 
with  excruciating  pain  in  the  abdomen,  and  all  the  symptoms  of  shock 
and  collapse. 

Cantharidin  is  absorbed  from  the  alimentary  canal,  and  also  to  a  less 
extent  from  the  skin,  but  has  no  important  action  on  the  internal 
organs,  with  the  exception  of  those  by  which  it  is  eliminated.  The 
heart  is  often  accelerated  in  poisoning  in  animals,  but  has  been  slowed 
in  some  cases  in  man,  while  in  others  it  was  rapid  and  feeble.  The 
respiration  becomes  rapid  and  dyspnoeic  some  time  before  death,  and 
some  confusion,  deepening  into  coma  and  convulsions,  may  indicate  a 
specific  action  on  the  central  nervous  system.  Vomiting  also  occurs 
on  subcutaneous  injection,  but  the  presence  of  ulceration  of  the  stomach 
and  of  diarrhoea  when  it  is  absorbed  from  the  skin,  indicates  that  some 
of  the  poison  is  excreted  into  the  alimentary  tract,  and  the  vomiting  in 
these  cases  may  therefore  be  of  peripheral  rather  than  of  central  origin. 
In  the  process  of  excretion,  cantharidin  has  the  same  effects  on  the 
organs  involved  as  on  those  of  absorption.  These  effects  are  seen 
only  in  the  genito-urinary  tract  in  the  vast  majority  of  cases  of  poison- 
ing. Comparatively  small  quantities  irritate  the  bladder,  and  cause  a 
constant  desire  to  micturate,  with  pain  in  doing  so.  In  somewhat 
larger  amount  it  sets  up  an  acute  nephritis  with  alburninuria,  pain  in 
the  kidney  region,  and  sometimes  blood  in  the  urine.  The  inflam- 
mation of  the  bladder  and  urethra  produces  intense  pain  and  often 
priapism  ;  in  women  abortion  is  said  to  occur  occasionally,  and  in  both 
sexes  the  irritation  may  lead  to  increased  sexual  desire. 

The  irritation  of  the  kidneys  by  small  doses  increases  their  secretion, 
and  cantharides  was  therefore  considered  a  diuretic  formerly.  The 
tendency  to  produce  nephritis  renders  it  a  dangerous  internal  remedy, 
however,  and  its  diuretic  power  is  quite  insignificant  in  comparison 
with  that  of  caffeine. 

Animals  vary  very  considerably  in  the  degree  in  which  they  react 
to  cantharidin,  the  most  noted  example  being  the  hedgehog,  which  is 
capable  of  surviving  a  dose  of  the  poison  sufficient  to  poison  an  adult 


SKIN  IRRITANTS  AND  COUNTER-IRRITATION.  91 

man.  Fowls  and  rabbits  also  possess  a  high  degree  of  congenital 
tolerance  for  this  poison,  although  none  of  these  is  absolutely  insus- 
ceptible to  it. 

PREPARATIONS. 

Cantharis  (U.  S.  P.,  B.  P.),  Spanish  Fly,  the  dried  beetle,  Cantharis  vesi- 
catoria. 

CERATUM  CANTHARIDIS  (U.  S.  P.). 

Collodium  Cantharidatum  (U.  S.  P.). 

Tinctura  Cantharidis  (U.  S.  P.,  B.  P.),  0.1-0.3  c.c.  (2-5  mins.). 

EMPLASTRUM  CANTHARIDIS  (B.  P.). 

EMPLASTRUM  CALEFACIENS  (B.  P.),  warming  plaster. 

Acetum  Cantharidis  (B.  P.). 

Unguentum  Cantharidis  (B.  P.). 

Collodium  Vesicans  (B.  P.). 

Liquor  Epispasticus  (B.  P.). 

Therapeutic  Uses. — Cantharides  is  at  present  used  almost  exclusively 
as  a  skin  irritant,  and  more  particularly  as  a  vesicant.  In  the  United 
States  the  cerate  is  generally  used  for  this  purpose,  and  is  applied  to 
the  skin  by  means  of  adhesive  plaster ;  the  corresponding  preparation 
of  the  B.  P.  is  the  cantharides  plaster.  It  is  to  be  noted  that,  in  order 
to  produce  actual  blistering,  the  plaster  has  to  remain  in  contact  with 
the  skin  some  8-10  hours,  but  an  equal  effect  may  be  achieved  by  re- 
placing the  plaster  by  a  hot  poultice  after  4—6  hours,  when  the  skin 
irritation  has  reached  the  stage  of  redness.  Cantharides  is  also  used  to 
cause  rubefaction  and  commencing  vesication  (flying  blister) ;  this  may 
be  done  by  the  use  of  these  preparations,  or  by  means  of  the  warming 
plaster,  B.  P.  Blistering  collodion  is  used  rarely  in  unmanageable 
cases  in  which  there  is  a  risk  of  the  plaster  being  removed  by  the 
patient.  The  ointment  is  said  to  induce  blistering  sooner  than  the 
plaster. 

Cantharidin  is  liable  to  be  absorbed  from  the  skin,  and  its  applica- 
tion is  therefore  avoided  where  there  is  any  tendency  to  renal  inflam- 
mation. 

Cantharides  has  been  used  not  infrequently  as  an  aphrodisiac,  and 
several  cases  of  poisoning  have  occurred  from  its  administration  for  this 
purpose.  In  cattle  it  is  largely  employed  to  this  end  in  some  coun- 
tries, and  in  man  it  has  undoubtedly  similar  effects  in  some  cases 
through  the  irritation  of  the  bladder  and  urethra,  but  its  use  for  this 
purpose  is  always  liable  to  produce  nephritis.  As  an  emmenagogue, 
cantharides  has  a  certain  popular  reputation,  which  however  has  been 
shown  to  be  unmerited,  any  influence  which  it  may  possess  on  the 
menstrual  flow  being  quite  insignificant,  and  probably  due  only  to  the 
irritation  of  the  bladder  and  urethra. 

Cantharides  has  been  advised  internally  in  some  forms  of  renal  and  vesical 
disease,  but  it  is  an  exceedingly  dangerous  remedy  in  these  conditions.  In 
1891,  Liebreich  proposed  the  treatment  of  tuberculous  affections  with  can- 
tharidinates,  in  the  belief  that  these  would  cause  an  inflammatory  reaction 
around  the  diseased  nodules,  and  would  thus  lead  to  their  being  destroyed 
or  encapsuled  in  cicatricial  tissue.  It  has  not  been  determined  whether 


92  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

cantharidin  acts  more  powerfully  on  irritated  tissues,  such  as  those  around 
the  tubercles,  but  experience  has  shown  that  no  benefit  followed  Liebreich's 
treatment,  while  in  several  cases  severe  nephritis  resulted  from  the  injection, 
and  the  method  has  therefore  fallen  into  disuse. 

Cantharides  is  sometimes  a  constituent  of  hair  washes,  its  irritant  action 
on  the  skin  being  credited  with  causing  a  more  rapid  growth  of  the  hair. 

In  cases  of  Poisoning  with  cantharides,  the  stomach  ought  to  be 
emptied  as  rapidly  as  possible  by  the  stomach  tube,  provided  the 
oesophagus  allows  of  its  passage.  Demulcents  and  albuminous  sub- 
stances are  of  use  in  slowing  the  absorption,  but  all  oily  or  fatty 
bodies  must  be  avoided,  as  they  tend  to  dissolve  the  cantharidin  and 
thus  promote  its  absorption.  Opium  may  be  given  for  the  pain,  and 
if  collapse  sets  in,  the  ordinary  measures  must  be  taken  to  combat  it. 

Poison  Ivy  and  Poison  Oak. — The  commonest  form  of  poisoning  in 
the  United  States  is  the  skin  eruption  produced  by  the  leaves  of  poison 
ivy  and  poison  oak  (Rhus  toxicodendron  and  venenata)  which  Pfaif 
has  recently  shown  to  be  due  to  the  presence  of  a  neutral  body,  Toxi- 
codendrol,  resembling  closely  the  other  members  of  this  group.  The 
effects  of  poison  ivy  can  arise  only  from  touching  the  plant,  the  poison- 
ous principle  not  being  volatile.  Very  minute  quantities  of  toxico- 
dendrol  are  sufficient  to  produce  skin  eruptions,  however,  y-flVo  m&* 
causing  distinct  symptoms  in  susceptible  persons.  The  popular  belief 
that  skin  affections  can  be  induced  by  approaching  the  plant,  without 
actually  touching  it,  is  probably  accounted  for  by  the  facts  that  the 
eruption  may  be  very  late  in  making  its  appearance,  and  that  poison 
ivy  is  very  frequently  mistaken  for  harmless  climbing  plants. 

In  the  dermatitis  from  poison  ivy,  Pfaff  recommends  that  the  skin 
be  washed  and  scrubbed  with  soap  and  water,  or  with  alcohol,  or  a 
solution  of  lead  acetate  in  alcohol.  Ointments  and  oily  liniments  are  to 
be  avoided,  as  they  dissolve  the  toxicodendrol  and  tend  to  spread  it 
over  the  skin  and  thus  produce  further  inflammation.  For  the  same 
reason,  the  alcohol  used  to  wash  the  part  must  be  removed  entirely,  as 
the  poisonous  principle  is  soluble  in  it,  while  insoluble  in  water. 

Several  little  known  substances  may  be  classed  along  with  cantharidin, 
which  they  resemble  in  their  violently  irritating  effects  on  the  skin  and 
mucous  membranes,  and  in  being  non-volatile.  They  are  of  little  impor- 
tance in  therapeutics,  but  not  infrequently  give  rise  to  accidental  poisoning, 
A  number  of  the  Ranunculaceae  order  are  irritants,  and  this  has  been  be- 
lieved to  be  due  to  their  containing  Anemonin,  C10H8O4,  which  is  closely  con- 
nected to  cantharidin  in  its  chemical  structure,  but  this  has  been  disputed 
recently  by  Brondgeest,  who  asserts  that  this  body  is  a  convulsive  poison. 
Noel  and  Lambert  also  state  that  anemonin  is  not  the  irritant  contained  in 
Anemone  pulsatilla,  which  owes  its  irritant  effects  to  some  other  more 
poisonous  constituent.  In  Mezereum,  Buchheim  found  an  anhydride  which 
he  termed  Mezerein,  but  Springenfeldt  states  that  the  action  is  due  to  an  oil 
and  to  the  acid  which  it  contains,  which  resemble  croton  oil  and  crotonoleic 
acid  in  their  effects.  Cardol,  found  in  the  fruits  of  Anacardium  occidentale 
and  in  Semecarpus  anacardium,  is  a  very  powerful  irritant,  and  has  been  used 
to  a  limited  extent  as  a  vesicant.  Cardol  is  probably  a  mixture  of  a  number 
of  substanceSj  but  it  is  unknown  to  which  of  these  it  owes  its  activity. 


VEGETABLE  PURGATIVES.  93 

Euphorbin  is  said  by  Buchheim  to  be  the  irritant  principle  in  the  Euphorbia 
resin  (Euphorbia  resinifera,  etc.),  and  to  resemble  cantharidin  in  its  anhy- 
dride form,  but  the  salts  and  the  euphorbic  acid  which  is  formed  from  them 
by  acids  are  inactive,  while  the  salts  of  cantharidic  acid  are  irritant,  and 
cantharidin  is  reformed  when  they  are  broken  up  by  acids.  A  very 
poisonous  member  of  the  Euphorbiaceee  is  the  Manicheel  tree,  growing  in 
the  West  Indies,  and  it  apparently  belongs  to  this  series. 

Capsicum  contains  one  or  more  non-volatile  irritant  substances  which 
probably  resemble  the  principles  of  this  series  more  closely  than  any  other. 
Capsicum  is  used  in  small  quantities  internally  and  has  therefore  been  men- 
tioned along  with  the  pepper  series,  but  it  is  also  used  occasionally  as  a  skin 
irritant.  Pepper  is  also  used  as  a  rubefacient  in  domestic  medicine. 

Chaulmoogra  Oil,  obtained  from  Gynocardia  odorata,  is  apparently  similar 
in  character  to  the  members  of  this  group,  although  it  is  less  irritant.  It 
is  used  externally  as  an  application  to  bruises,  and  both  externally  and 
internally  in  leprosy,  although  it  is  probably  of  little  avail  in  this  disease. 
It  is  said  to  owe  its  activity  to  Gynocardic  acid,  which  it  contains  in  combi- 
nation with  glycerin.  Croton  oil  is  also  used  as  a  skin  irritant,  but  will  be 
treated  of  in  connection  with  the  purgatives  (page  99). 

Many  other  plants  possess  irritant,  poisonous  properties,  which  would  ap- 
parently entitle  them  to  a  place  in  this  series,  but  so  little  is  known  of  their 
active  principles  and  of  their  effects,  that  they  may  be  omitted  for  the  present. 

PREPARATIONS. 

Mezereum  (U.  S.  P.),  Mezerei  Cortex  (B.  P.),  the  bark  of  Daphne  meze- 
reum  and  of  other  species. 

Fluidextractum  Mezerei  (U.  S.  P.). 

Mezereum  is  also  contained  in  several  of  the  sarsaparilla  preparations 
(U.  S.  P.). 

Capsicum  (U.  S.  P.,  B.  P.). 

Emplastrum  Capsici    (U.  S.  P.). 

Unguentum  Capsici  (B.  P.). 

(For  the  other  preparations  of  Capsicum  see  page  73.) 

BIBLIOGRAPHY. 

Radecki.     Inaug.  Diss.,  Dorpat,  1866. 

Aufrecht.     Centralbl.  f.  med.  Wissensch.,  1882,  pp.  545,  849. 
Eliaschoff.     Virchow's  Arch.,  xciv.,  p.  323. 

Liebreich.     Therap.  Monatsheft,  1891,  p.  169  ;  1892,  p.  294 ;  1895,  p.  167. 
Buchheim.     Arch.  d.  Heilkunde,  xiii.,  p.  1. 
Cot-nil.     Comptes  rendus  de  Facad.,  civ.,  p.  1875. 
Lewin.     Deutsch.  med.  Woch.,  1901,  p.  184. 
Pfaff.     Journ.  of  Exp.  Med.,  ii.,  p.  181.     ( Toxicodendrol. ) 
Springenfeldt.     Inaug.  Dis.,  Dorpat,  1890.     (Mezereum.) 
Brondgeest.     Schmidt's  Jahrbuch,  ccxx.,  p.  131.      (Anemonin. ) 
Noel  and  Lambert.     Arch,   de  Pharmacodynamique,   iv.,   p.    169.     (Pulsatilla  and 
anemonin. ) 

VII.     VEGETABLE   PURGATIVES. 

Purgatives  are  drugs  which  are  employed  in  medicine  to  evacuate 
the  bowel  of  its  contents.  Many  drugs  produce  evacuation  in  the 
course  of  their  action,  but  have  other  effects  of  importance  and  are  not 
included  in  this  class.  Thus  the  members  of  the  preceding  classes  of 
skin  irritants  induce  diarrhoea,  but  this  is  accompanied  by  irritation  of 
the  mouth,  throat  and  stomach,  and  in  many  other  forms  of  poisoning, 
diarrhoea  is  a  prominent  feature,  but  is  accompanied  by  vomiting  or 


94  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

some  other  symptom.  The  ideal  purgative  is  devoid  of  any  effects 
whatsoever,  save  in  the  intestine ;  it  passes  through  the  stomach  with- 
out materially  deranging  its  function,  and  is  not  absorbed,  or  at  any 
rate  is  absorbed  so  slowly  that  it  has  time  to  unfold  its  action  through- 
out the  intestine.  The  vegetable  purgatives  act  through  their  irritant 
properties,  which  in  some  instances  are  elicited  only  by  the  action  of 
the  secretion  of  the  intestines  and  of  the  neighboring  glands.  Thus 
some  of  the  purgatives  pass  through  the  stomach  in  the  form  of  bland, 
non-irritant  compounds  (castor  oil),  which  are  broken  up  by  the  diges- 
tive processes  in  the  intestine,  while  others  perhaps  owe  their  activity 
in  the  intestine  to  their  solution  or  suspension  in  the  juices. 

Many  classifications  of  the  purgatives  have  been  based  on  their 
effects,  and  some  of  the  terms  are  still  retained,  such  as  aperient,  ecco- 
protic,  laxative,  purgative,  cholagogue,  hydragogue,  cathartic  or  drastic. 
But  the  effect  of  the  purgatives  is  determined  largely  by  the  dose  and 
by  the  condition  of  the  intestine,  so  that  a  small  dose  may  act  as  an  ape- 
rient, laxative  or  eccoprotic,  while  a  larger  quantity  of  the  same  drug, 
or  even  the  same  dose  in  a  more  susceptible  individual,  may  act  as  a 
drastic  or  hydragogue  cathartic.  It  is,  therefore,  preferable  to  classify 
them  according  to  their  chemical  nature  as  far  as  that  is  known,  and 
in  this  way  three  classes  may  be  formed,  (1)  purgative  oils,  (2)  purga- 
tives of  the  anthracene  series,  (3)  the  jalapin  and  colocynthin  group. 

Symptoms. — In  moderate  doses  the  purgatives  simply  hasten  the 
normal  movements  of  the  intestines,  and  the  stool  is  of  the  ordinary  ap- 
pearance and  consistency  (laxative,  aperient,  or  eccoprotic  action).  In 
larger  quantities  they  cause  a  more  profuse  evacuation  than  normally, 
and  the  stools,  which  are  repeated  at  short  intervals,  are  of  a  looser, 
more  fluid  consistency.  Their  action  is  accompanied  by  considerable 
pain  and  colic,  and  the  hurried  movements  of  the  intestine  are  shown 
by  the  characteristic  gurgling  sounds.  Large  quantities  of  the  more 
powerful  purgatives  may  cause  all  the  symptoms  of  acute  enteritis ; 
the  stools  at  first  contain  the  ordinary  faecal  substances  accompanied 
by  more  fluid  than  usual,  but  later  consist  largely  of  blood-stained 
mucous  fluid  with  little  or  no  resemblance  to  ordinary  faeces.  This 
violent  purgation,  which  is  not  induced  in  therapeutics,  is  accompanied 
by  pain  and  tenderness  in  the  abdomen,  and  may  induce  shock,  col- 
lapse and  eventually  death. 

Action. — The  origin  of  the  fluid  of  the  stools  after  purgatives  has 
been  much  debated.  According  to  many  authors,  they  accelerate  the 
passage  of  the  intestinal  contents  so  much  that  there  is  no  time  for 
the  absorption  of  the  fluid,  and  the  faeces  escape  in  the  fluid  con- 
dition in  which  they  normally  exist  in  the  small  intestine.  Other  in- 
vestigators hold  that  purgatives  cause  fluid  to  pass  into  the  intestine, 
either  by  increasing  the  normal  secretions,  or  by  causing  an  inflam- 
matory exudate  from  the  vessels.  Both  parties  have  founded,  or  at- 
tempted to  confirm  their  statements  by  the  results  of  the  injection  of 
the  purgatives  into  loops  of  intestine  isolated  from  the  rest  of  the 
bowel.  In  these,  some  observers  (Brunton,  Roy)  have  found  a  larger 


VEGETABLE  PURGATIVES.  95 

accumulation  of  fluid  after  the  injection  of  the  purgatives,  while 
others  (Thiry,  Radziejewski)  found  no  more  fluid  after  purgatives  than 
after  indifferent  fluids.  These  contradictory  results  are  probably  due 
to  the  methods  adopted,  and  the  quantity  of  the  drug  injected.  In 
small  quantities,  such  as  are  used  in  the  vast  majority  of  cases  in  ther- 
apeutics, the  irritation  produced  by  the  purgatives  is  probably  only 
enough  to  accelerate  peristalsis  somewhat,  and  the  fluid  of  the  stools 
is  drawn  partly  from  the  food  and  partly  from  the  ordinary  secretions 
of  the  digestive  organs.  In  these  cases  the  intestine  is  not  actually 
inflamed,  although  some  congestion  may  occur  in  it,  as  in  all  organs 
in  a  state  of  abnormal  activity.  On  the  other  hand,  when  large  quan- 
tities are  ingested  a  true  inflammation  of  the  intestine  occurs,  mani- 
fested by  increased  movement,  congestion,  the  exudation  of  fluid  into 
the  lumen  of  the  bowel,  and  pain.  In  these  cases  the  intestine  pre- 
sents the  usual  signs  of  inflammation ;  it  is  red  and  congested,  and 
contains  a  muco-purulent  fluid  and  often  blood.  The  matter,  therefore 
resolves  itself  into  a  question  of  dose ;  if  it  be  small,  the  fluid  is  not 
an  exudate,  if  it  be  large  the  fluid  is  partly  an  inflammatory  product. 
The  stools  following  the  administration  of  purgatives  differ  from  the 
normal  faeces  in  containing  a  larger  proportion  of  water  and  also  of 
soluble  substances.  In  fact,  they  resemble  rather  the  contents  of  the 
small  intestine  than  the  normal  excreta,  and  contain  bodies  which 
would  normally  have  been  absorbed  and  utilized  but  which  have  been 
hurried  through  the  bowel  too  rapidly  to  permit  of  their  being  taken 
up  by  the  epithelium. 

The  colic  produced  by  purgatives  is  not  due  to  the  inflammation  of 
the  intestinal  wall,  but  is  probably  explained  by  the  more  vigorous 
contractions  of  the  walls  of  the  bowel  and  the  difficulty  in  forcing  on 
hard  faecal  masses  in  the  large  intestine.  The  tenderness  produced  by 
large  quantities  of  the  purgatives,  on  the  other  hand,  would  seem  to 
indicate  inflammation. 

There  is  every  reason  to  believe  that  purgation  may  be  induced  by 
reflexes  arising  from  the  stomach  or  skin,  or  from  localized  irritation 
of  one  part  of  the  bowel ;  and  these  reflexes,  in  some  instances  at 
least,  must  pass  by  way  of  the  central  nervous  system.  In  the  accel- 
erated peristalsis  ordinarily  induced  by  the  purgatives,  however,  the 
central  nervous  system  is  probably  not  involved  ;  the  irritation  of  the 
mucous  membrane  renders  it  more  sensitive  to  the  stimuli  which  it 
ordinarily  receives  from  the  contents,  and  the  nervous  impulses  result- 
ing from  these  are  transmitted  to  the  intestinal  nervous  plexus  and 
give  rise  to  the  reflex  inhibition  and  contraction  of  the  muscular  coats 
by  which  the  peristaltic  movement  is  carried  out.  This  action  of  the 
purgatives  in  increasing  the  irritability  of  the  mucous  membrane 
probably  extends  throughout  the  bowel,  and  the  movements  of  both 
the  small  and  the  large  intestine  are  accelerated.  There  is  no  reason 
to  suppose  that  the  food  is  retarded  in  its  passage  through  the  small 
bowel  in  constipation ;  the  delay  takes  place  in  the  colon,  and  it  is  in 


96  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

increasing  the  irritability  and  removing  the  sluggishness  of  the  latter 
that  purgatives  are  beneficial. 

The  action  of  the  purgatives  is  generally  considered  purely  local,  and 
strictly  analogous  to  that  of  the  skin-irritants.  The  irritation  of  the 
epithelium  and  of  the  nerve-ends  leads  reflexly  to  increased  activity  of 
the  deeper  layers,  which  manifests  itself  in  the  bowel  by  contraction  of 
the  muscle,  in  the  skin  by  hypersemia.  But  some  of  the  purgatives 
seem  to  have  a  further  action,  which  is  of  a  more  specific  nature. 
Thus  senna,  aloin,  frangnlin,  and  colocynthin  cause  evacuation  of  the 
bowel  when  injected  subcutaneously  or  into  the  blood,  podophyllum 
resin  causes  violent  purging  and  vomiting  when  thus  administered,  and 
croton  oil  has  long  been  rubbed  on  the  skin  in  order  to  relieve  con- 
stipation, and  is  found  to  cause  intestinal  inflammation  and  purging 
when  injected  intravenously.  It  has  accordingly  been  suggested  that 
these  have  a  specific  action  on  the  bowel  quite  apart  from  their  irri- 
tant effects  ;  but  it  is  quite  possible  that  their  intestinal  effects  are  here 
due  to  their  excretion  into  the  bowel,  which  has  been  shown  to  occur 
in  several  instances.  Other  irritants  applied  subcutaneously  or  intra- 
venously often  produce  similar  effects  on  the  alimentary  canal. 

The  interval  which  elapses  between  the  administration  of  a  purga- 
tive and  its  effects  varies  with  the  dose,  and  also  with  the  individual 
drug.  In  ordinary  therapeutic  doses,  evacuation  of  the  bowels  occurs 
in  most  cases  in  5-10  hours,  but  if  large  quantities  of  the  more  pow- 
erful purges,  such  as  jalap  or  croton  oil,  be  given,  the  effects  may  be 
elicited  in  two  hours.  Aloes  and  podophyllum  differ  from  the  others 
in  the  length  of  the  interval,  catharsis  rarely  or  never  occurring  ear- 
lier than  10-12  hours  after  their  administration,  and  often  only  after 
20-24  hours. 

The  movement  of  the  intestine  induced  by  purgatives  is  accom- 
panied by  an  increase  in  the  leucocytes  of  the  blood  similar  to  that 
observed  in  other  forms  of  intestinal  activity,  e.  g.,  during  digestion. 

The  effects  of  the  purgatives  vary  greatly  in  different  animals. 
Thus,  the  rabbit  is  very  refractory  to  most  of  the  series,  and  often  is 
killed  by  intestinal  irritation  without  any  evacuation  being  produced. 
The  frog  is  unaffected  by  quantities  which  would  produce  poisoning  in 
man,  while  the  dog  and  cat  respond  much  more  readily. 

It  was  formerly  supposed  that  purgatives  increased  the  secretion  of 
bile,  and  certain  of  them,  which  were  believed  to  have  a  special  activity 
in  this  direction,  were  known  as  Cholagogues.  It  has  been  shown  of 
recent  years  that  none  of  them  possesses  any  action  on  the  secretion  of 
bile,  although  they  may  increase  its  excretion  by  hurrying  it  through 
the  intestine  and  preventing  its  reabsorption.  On  the  other  hand,  the 
presence  of  bile  in  the  intestine  is  a  condition  necessary  to  the  activity 
of  many  of  the  purgatives.  Thus  Buchheim  and  Stadelmann  found 
that  in  the  absence  of  bile  the  following  purgatives  are  either  quite  in- 
active or  very  much  less  powerful  than  usual — podophyllum  and  podo- 
phyllotoxin,  resin  of  jalap,  convolvulin,  resin  of  scammony,  rhubarb, 
cathartic  acid,  and  the  sodium  salt  of  gambogic  acid.  This  is  prob- 


VEGETABLE  PURGATIVES.  97 

ably  due  to  some  solvent  action  of  the  bile,  for  Stadelmann  found  that 
when  soaps  were  given  with  some  of  these  drugs  their  activity  returned, 
and  in  other  cases  a  comparatively  slight  modification  of  their  chemical 
form  was  sufficient  to  restore  their  activity,  even  in  the  absence  of 
either  bile  or  soap.  Analogous  results  have  been  observed  from  other 
causes  than  the  absence  of  bile ;  thus  some  of  the  pure  principles  of 
the  purgatives  are  much  less  active  than  the  crude  drugs  because  the 
impurities  of  the  latter  alter  their  solubility.  This  alteration  of  the 
solubility  may  act  in  two  ways  :  if  the  principle  is  rendered  too  soluble, 
it  may  be  absorbed  in  the  stomach  and  upper  part  of  the  bowel,  and 
therefore  fail  to  produce  purgation ;  on  the  other  hand,  it  may  be 
rendered  so  insoluble  that  it  fails  to  come  into  intimate  contact  with 
the  bowel  wall,  and  therefore  does  not  irritate  it.  The  effects  of  such 
colloid  substances  as  the  bile  and  gums  is  to  delay  the  absorption  of 
soluble  substances  in  the  upper  part  of  the  bowel,  and  at  the  same 
time  to  keep  the  insoluble  resins  in  suspension  (Tappeiner). 

Few  of  the  purgatives  have  any  appreciable  action  after  absorption, 
but  general  effects  may  be  produced  indirectly  from  their  intestinal 
action.  It  is  probable  that  reflexes  are  elicited  by  irritation  of  the 
bowel  analogous  to  those  discussed  under  skin  irritants,  but  in  addition, 
the  congestion  of  the  bowel  produced  by  its  activity  must  alter  con- 
siderably the  distribution  of  the  blood  in  the  body.  The  belief  in  the 
efficacy  of  a  purge  in  congestion  of  the  brain  may  thus  be  based  on  a 
true  "  revulsive  "  action  ;  for  the  dilation  of  the  intestinal  vessels  must 
necessarily  lessen  the  blood  pressure  and  thereby  the  blood  supply  to 
the  brain.  The  congestion  of  the  intestine  is  accompanied  by  a  similar 
condition  in  the  other  pelvic  organs,  and  the  purgatives  therefore  often 
cause  congestion  of  the  uterus,  with  excessive  menstrual  flow,  or  in  the 
case  of  pregnant  women,  abortion.  Lastly,  a  certain  amount  of  fluid 
is  withdrawn  which  would  otherwise  be  excreted  by  the  urine,  which 
is  found  to  be  proportionately  diminished  in  amount. 

1.   The  Purgative  Oils. 

Two  very  important  members  of  the  purgative  series  are  Castor  oil 
(Oleum  Ricini),  and  Croton  oil  (Oleum  Tiglii  or  Crotonis).1  Castor  oil 
consists  almost  entirely  of  an  oil  which  resembles  olive  oil  in  most  re- 
spects, but  on  saponification  forms  ricinoleic  acid  instead  of  oleic  acid. 
This  acid  (C17H32(OH)COOH)  differs  from  the  fatty  acids  obtained 
from  ordinary  oils  in  being  unsaturated  and  in  containing  a  hydroxyl 
group.  Castor  oil  is  itself  a  bland,  non-irritating  fluid,  but  on  passing 
into  the  intestine  is  decomposed  by  the  digestive  juices,  and  the 
ricinoleates  thus  formed  are  irritant  and  cause  purgation.  When  the 
oil  is  saponified,  and  the  free  acid  given  by  the  mouth,  the  effects 
are  quite  different  from  those  of  the  oil,  for  the  taste  is  acrid  and  un- 
pleasant, and  discomfort,  nausea  and  vomiting  may  follow  its  in- 

1  Another  plant  containing  a  purgative  oil  is  the  Jatropha  curcas,  which  bears  the 
Barbadoes  nuts,  or  purging  nuts.     It  is  somewhat  weaker  in  its  action  than  croton  oil, 
and  is  said  to  be  often  substituted  for  it  in  specimens  of  croton  oil  obtained  from  India, 
7 


98  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

gestion  from  its  irritant  action  on  the  stomach.  The  oil,  on  the  other 
hand,  has  a  bland,  if  unpleasant,  taste,  and  produces  no  effects  on 
the  stomach.  Several  other  esters  of  ricinoleic  acid  have  been  shown 
by  Meyer  to  resemble  the  glycerin  ester  (castor  oil)  in  their  purgative 
effects. 

Croton  oil  is  decomposed  into  glycerin  and  crotonoleic  acid,  of  which 
little  is  known  except  that  it  is  similar  to  ricinoleic  acid  from  a  chemical 
point  of  view.  It  differs  from  it  in  the  fact  that  crotonoleic  acid  is  a 
much  more  irritant  body,  and  in  that  some  acid  is  found  free  in  the  oil. 
This  free  acid  renders  croton  oil  irritant  before  it  reaches  the  intestine, 
although  the  same  process  goes  on  here  as  in  castor  oil,  and  the  croton 
oil  therefore  becomes  more  irritant  than  elsewhere.  On  the  skin,  and 
in  the  throat  and  stomach,  croton  oil  exerts  its  irritant  action,  but  these 
effects  may  be  avoided  while  it  continues  to  act  as  a  purgative,  if  the 
free  acid  be  removed.  Croton  oil  then  becomes  bland  and  non-irritant, 
and  can  be  distinguished  from  castor  oil  only  by  its  more  powerful  pur- 
gative action.  Castor  oil  is  absorbed  from  the  intestine  and  disappears 
in  the  tissues  in  the  same  way  as  an  ordinary  oil.  Nothing  is  known 
with  certainty  of  the  fate  of  croton  oil  in  the  body,  but  it  is  not  un- 
likely that  it  is  excreted  in  part  into  the  large  intestine.  Both  croton 
oil  and  castor  oil  are  borne  in  much  larger  quantities  by  animals  than 
by  man,  and  not  infrequently  the  former  causes  acute  enteritis  without 
purgation. 

Castor  oil  may  be  given  in  very  large  quantities  without  producing 
any  symptoms,  save  those  of  a  mild  laxative.  Croton  oil,  on  the  other 
hand,  acts  as  an  irritant  poison  in  any  save  the  smallest  doses,  pro- 
ducing vomiting  and  violent  purging  with  bloody  stools,  collapse  and 
death.  Castor  oil  is  occasionally  used  as  an  emollient  to  the  skin, 
and  has  been  employed  as  a  solvent  for  application  to  the  eye,  while 
croton  oil  has  already  been  mentioned  as  a  pustulant.  The  harmless 
nature  of  castor  oil  is  shown  by  its  use  in  China  as  an  article  of 
diet. 

It  was  formerly  a  matter  of  dispute  whether  croton  oil  causes  the  formation 
of  pus  when  injected  subcutaneous! y,  or  whether  the  presence  of  microbes  is 
necessary,  but  it  seems  unquestionable  now  that  croton  oil  alone  is  capable  of 
producing  this  effect,  provided  that  it  contains  free  crotonoleic  acid.  The 
contradictory  results  obtained  by  observers  may  be  explained  by  the  fact 
that  croton  oil  occasionally  contains  very  little  free  acid,  and  that  the 
mammalian  tissues  are  unable  to  saponify  the  oil  save  in  the  presence  of  the 
intestinal  ferments.  In  the  frog  these  ferments  are  present  in  the  tissues,  or 
perhaps  the  latter  are  capable  of  breaking  up  the  oil,  for  Hirschheydt  found 
that  the  neutral  oil  caused  inflammation  and  hemorrhages  in  various  parts 
of  the  body. 

In  the  beans  from  which  castor  oil  and  croton  oil  are  derived,  toxalbumins 
are  found,  and  these  were  at  one  time  supposed  to  be  the  active  principles 
of  the  oils.  (See  Ricin.)  It  has  been  shown,  however,  that  the  oils  are  en- 
tirely free  from  these  poisons,  and  that  their  action  is  due  solely  to  the  acids 
of  which  they  are  glycerides. 


VEGETABLE  PURGATIVES.  99 

PREPARATIONS. 

OLEUM  RICTNI  (U.  S.  P.,  B.  P.),  a  fixed  oil  expressed  from  the  seed,  or 
bean  of  Ricinus  communis.  Dose,  4-30  c.c.  (1-8  fl.  drs.). 

Mistura  Olei  Ricini  (B.  P.),  made  up  with  cinnamon  and  orange  flower 
water  by  means  of  mucilage,  1-2  fl.  oz. 

OLEUM  TIGLII  (U.  S.  P.),  OLEUM  CROTONIS  (B.  P.),  a  fixed  oil  expressed 
from  the  seed  of  Croton  Tiglium.  Dose,  0.02-0.05  c.c.  (\-\  m.). 

Castor  oil  is  difficult  to  take  owing  to  its  unpleasant  taste.  It  may  be 
given  alone,  in  an  emulsion  flavored  with  sugar  and  some  volatile  oil,  in 
wine,  spirits  or  glycerin,  or  in  flexible  capsules. 

Croton  oil  is  often  given  in  a  pill  made  up  with  bread  crumb,  or  a  single 
drop  may  be  given  on  a  lump  of  sugar  or  in  solution  in  castor  oil. 

2.   The  Anthracene  Purgatives. 

A  number  of  purgatives,  Rhubarb,  Senna,  Aloes  and  Frangula,  owe 
their  activity  to  the  presence  of  irritant  anthracene  (C14H10)  compounds, 
only  a  few  of  which  have  been  isolated.  The  chemical  examination  of 
these  drugs  is  a  matter  of  great  difficulty,  as  they  each  contain  several 
active  principles  which  are  very  nearly  related  to  each  other,  and 
some  of  which  are  undoubtedly  the  products  of  the  decomposition  of 
more  complex  bodies.  In  addition,  several  of  the  pure  substances 
have  been  found  to  be  less  certain  in  their  purgative  action  than  the 
crude  drugs,  probably  because  the  colloids  in  the  latter  aid  in  their 
solution. 

All  those  which  have  been  completely  isolated  hitherto  have  proved  to  be 
derivatives  of  anthraquinone, 

CH      CH      CH  CH      CH      CH 

c  /\  c  /\  /\  c 

HC/    \ 


HC/      \/         '         N'CH  HC-  •'         '  'CH 


HC\    A.    /\    yen 

,/^  \ 


/\c/\c/\ 

HC/      NX      Y         |CH 

HC\/c\/c\/CH 

CH      CO      CH 


C 

CH      CH      CH  CH      CO      CH 

Anthracene.  Anthraquinone. 

and  some  of  the  oxyanthraquinones  seem  to  be  widely  distributed.  Thus  all 
the  members  of  the  group  contain  Emodin  or  trioxymethylanthraquinone, 
(CUH4(CH3)(OH)3O2),  and  rhubarb  and  senna  contain  Chrysophanic  acid  or 
dioxymethylanthraquinone,  (CUH5(CH3)(OH)2O2),  while  a  nearly  related 
body  has  been  found  in  Frangula.  It  is  still  undecided  whether  the  emodin 
found  in  different  drugs  is  identical  or  merely  isomeric,  and  the  same  may 
be  said  in  regard  to  curysophanic  acid.  In  addition,  a  number  of  other  an- 
thracene bodies  occur  in  these  purgatives,  some  of  them  combined  with 
sugars  to  form  glucosides,  but  little  is  known  regarding  them,  and  it  seems 
likely  that  some  may  prove  to  be  impure  emodin.  Acid  glucosides  have 
been  found  in  rhubarb,  senna  (Cathartin  or  Cathartinic  acid)  and  in  cascara 
and  frangula  (Cathartin  and  Frangulin).  In  the  different  species  of  aloes 
several  Aloins  (Barbaloin  from  Barbadoes  aloes,  Socaloin  from  Socotrine  aloes, 
etc.)  have  been  isolated. 

Several  of  the  pure  principles  have  been  used  as  purgatives,  although 
they  seem  on  the  whole  to  be  less  certain  in  their  effects  than  the  crude 
drugs.  Chrysophanic  acid  does  not  cause  purgation,  owing  to  its  rapid 
absorption.  Frangulin  has  given  satisfactory  results,  and  Cathartin  has 


100  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

also  been  used  experimentally,  but  is  very  liable  to  undergo  decompo- 
sition. Aloin  is  less  certain  in  its  effects  than  aloes,  and  it  seems  to  be 
indisputable  that  the  crystalline  aloin  itself  is  inactive  in  the  bowel,  but 
is  there  changed  under  certain  conditions  to  an  amorphous  compound 
which  has  irritant  effects.  This  active  substance  can  be  prepared  from 
aloin  by  boiling  in  water,  and  may  be  present  in  the  amorphous  resin  left 
after  the  extraction  of  aloin.  The  purgative  action  of  aloes  is  increased 
by  the  addition  of  small  quantities  of  alkaline  salts  and  of  iron.  The 
presence  of  bile  in  the  intestine  is  not  necessary  to  elicit  the  action  of 
this  group,  except  perhaps  in  the  case  of  rhubarb ;  enemata  of  aloes 
are  inactive  unless  bile  is  injected  with  them,  but  Kohlstock  found  that 
the  same  results  could  be  attained  by  dissolving  aloin  in  glycerin. 
The  latter  produces  evacuation  when  injected  alone  as  an  enema,  it  is 
true,  but  he  used  smaller  quantities  of  it  than  are  necessary  for  pur- 
gation, so  that  the  role  played  by  the  bile  is  probably  the  same  as  that 
of  glycerin — a  purely  solvent  one. 

The  absorption  of  these  bodies  has  not  been  satisfactorily  determined 
in  most  cases.  The  urine  is  rendered  yellow  after  rhubarb  and  senna, 
owing  to  the  absorption  and  excretion  of  chrysophanic  acid,  but  it  is 
questionable  whether  the  more  active  principles  pass  into  the  urine  in 
appreciable  amounts.  When  aloin  is  injected  subcutaneously  or  intra- 
venously, it  is  excreted  for  the  main  part  into  the  bowel,  and  there  pro- 
duces irritation  and  catharsis.  Cathartin  and  frangulin  also  act  as 
purgatives  when  they  are  injected  subcutaneously,  probably  because 
they  are  excreted  into  the  bowel,  although  this  has  not  as  yet  been 
investigated.  The  yellow  pigment  of  the  urine  after  rhubarb  and 
senna  becomes  a  purple  red  on  the  addition  of  alkalies  * ;  the  milk  and 
skin  also  are  said  to  assume  a  yellowish  tinge  from  the  presence  of 
chrysophanic  acid. 

In  the  rabbit  aloin  seldom  causes  purgation,  and  is  excreted  by  the 
kidney  in  considerable  quantity,  especially  when  injected  hypoder- 
mically.  In  passing  through  this  organ  it  causes  marked  irritation 
and  epithelial  necrosis,  which  often  proves  fatal  in  a  few  days.  No 
irritation  of  the  kidney  occurs  in  man,  the  dog,  or  the  cat  after  aloin. 

Rhubarb  contains  a  considerable  amount  of  tannic  acid,  which  acts 
as  an  astringent  and  therefore  tends  to  cause  constipation  after  the 
evacuation  of  the  bowels.  It  is  not  well  tolerated  in  some  cases,  its 
administration  being  followed  by  nausea,  headache  and  giddiness,  more 
rarely  by  skin  eruptions  of  different  kinds. 

PREPARATIONS. 

U.  S.  P.—  Rheum,  rhubarb,  the  root  of  Rheum  officinale. 
EXTRACTUM  RHEI,  0.3-0.6  G.  (5-10  grs.). 
Fluidextractum  Ehei,  1-2  c.c.,  (15-30  mins.). 

PILUL^E  RHEI  COMPOSITE  (aloes,  myrrh  and  oil  of  peppermint),  1-5  pills. 
PULVIS  RHEI  COMPOSITUS  (Gregory's  Powder)  contains  magnesia  and  ginger. 
Dose,  1-4  G.  (20-60  grs.). 

Tinctura  Rhei,  4-16  c.c.  (1-4  fl.  drs.). 

1  For  the  reactions  required  to  distinguish  cliiysophanic  acid  in  the  urine  from  the 
pigment  occurring  in  it  after  santonin,  see  page  122. 


'VEGETABLE  PURGATIVES.  101 

Tinctura  Rhei  Aromatica  (contains  several  volatile  oils),  2-8  e.c.  (£-2  fl.  drs.). 
Mistura  Rhei  et  Sodse  (contains  bicarbonate  of  soda,  ipecac,  peppermint 
and  glycerin),  10-100  c.c.  (2  fl.  drs.-3  oz.). 


AROMATICUS 

B.  P.  —  Rhei  Radix,  rhubarb  root,  the  erect  rhizome  or  so-called  root  of 
Rheum  palmatum  ;  3-10  grs.  for  repeated  administration  ;  for  a  single  ad- 
ministration, 15-30  grs. 

EXTRACTUM  RHEI,  2-8  grs. 

PILULA  RHEI  COMPOSITA  (contains  rhubarb,  Socotrine  aloes,  myrrh,  and 
oil  of  peppermint),  4-8  grs. 

PULVIS  RHEI  COMPOSITUS  (Gregory's  Powder)  contains  rhubarb,  light 
magnesia  and  ginger,  20-60  grs. 

TINCTURA  RHEI  COMPOSITA,  formed  from  rhubarb,  cardamom  and  cori- 
ander, |-1  fl.  dr.  for  repeated  administration  ;  2-4  fl.  drs.  for  a  single  ad- 
ministration. 

SYRTJPUS  RHEI,  £-2  fl.  drs. 

Infusum  Rhei,  5—  1  fl.  oz. 

Liquor  Rhei  Concentrates,  £-1  fl.  dr. 

U.  S.  P.—  Senna,  the  leaflets  of  Cassia  acutifolia  (Alexandria  Senna),  and 
of  Cassia  angustifolia  (India  Senna). 

CONFECTIO  SENXJE  contains  senna,  cassia  fistula,  tamarind,  prune,  fig,  sugar, 
and  oil  of  coriander,  4—8  G.  (1-2  drs.). 

Fluidextractum  Sennce,  4-8  c.c.  (1-2  fl.  drs.). 

INFUSUM  SENNCE  COMPOSITUM  (Black  Draught)  contains  senna,  manna, 
magnesium  sulphate  and  fennel,  60-120  c.c.  (2-4  fl.  oz.). 

SYRUPUS  SENN.E,  4-16  c.c.  (1-4  fl.  drs.). 

Senna  is  also  contained  in  the  compound  syrup  of  sarsaparilla  and  in  the 
compound  liquorice  powder. 

Senna  is  often  administered  as  a  simple  infusion,  senna  tea,  a  teaspoonful 
of  the  leaves  being  used  in  a  cupful  of  water. 

B.  P.  —  Senna  Alexandrina,  the  dried  leaflets  of  Cassia  acutifolia. 

Senna  Indica,  Tinnivelly  senna,  the  dried  leaflets  of  Cassia  angustifolia. 

TINCTURA  SENNJE  COMPOSITA,  formed  from  senna,  raisins,  caraway,  and 
coriander,  $-1  fl.  dr.  for  repeated  administration  ;  2-4  fl.  drs.  for  a  single 
administration. 

SYRUPUS  SENN^:,  £-2  fl.  drs. 

Liquor  Sennse  Concentratus,  £-1  fl.  dr. 

INFUSUM  SENN^E,  £-1  fl.  oz.  ;  as  a  draught,  2  fl.  oz. 

MISTURA  SENNCE  COMPOSITA  (Black  Draught),  formed  from  magnesium 
sulphate,  liquorice,  compound  tincture  of  cardamom,  aromatic  spirit  of 
ammonia,  and  infusion  of  senna,  £-2  fl.  oz. 

CONFECTIO  SENN.E,  formed  of  senna,  coriander,  figs,  tamarinds,  cassia, 
prunes,  liquorice,  and  sugar,  60-120  grs. 

U.  S.  P.  —  Aloe,  the  inspissated  juice  of  the  leaves  of  several  species  of  aloe. 
.  Aloe  Purificata,  aloes  from  which  insoluble  impurities  have  been  removed, 
0.1-0.5G.  (2-7  grs.). 

Aloinum,  a  neutral  principle  obtained  from  aloes,  0.05-0.2  G.  (1-4  grs.). 

EXTRACTUM  ALOES,  0.1-0.5  G.  (2-7  grs.). 

PILULE  ALOES,  1-5  pills. 

PILUL^E  ALOES  ET  FERRI,  1-5  pills. 

Pilulce  Aloes  et  Mastiches,  1—5  pills. 

Pilulce  Aloes  et  Myrrhce,  1—5  pills. 

Pilulce  Laxativce  Compositce  (aloin,  strychnine,  belladonna  and  ipecacuanha), 
2  pills. 

TINCTURA  ALOES,  2-8  c.c.  (£-2  fl.  drs.). 

Tinctura  Aloes,  et  Myrrhce,  2-8  c.c.  (J-2  fl.  drs.). 

Aloes  is  also  contained  in  compound  rhubarb  pill,  compound  extract  of 
colocynth,  and  compound  tincture  of  benzoin. 


102  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

B.  P.— Aloe  Barbadensis,  the  juice  of  Aloe  vera  and  other  species,  Bar 
badoes  Aloes  or  Curacoa  Aloes,  2-5  grs. 

Aloe  Socotrina,  the  juice  of  Aloe  Perry i,  Socotrine  or  Zanzibar  Aloes. 

Aloinum,  J-2  grs. 

EXTRACTUM  ALOES,  1-4  grs. 

PILULA  ALOES,  4-8  grs. 

Pilula  Aloes  Socotrinse,  4-8  grs. 

PILULA  ALOES  ET  FERRI,  4-8  grs. 

PILULA  ALOES  ET  ASAFETID^E,  4-8  grs. 

Pilula  Aloes  et  Myrrhse,  4-8  grs. 

TINCTURA  ALOES,  J-l  fl.  dr.  for  repeated  doses;  fora  single  dose,  l£-2  fl.  drs. 

Decoctum  Aloes  Compositum  (aloes,  myrrh,  saffron,  potassium  carbonate, 
liquorice,  compound  tincture  of  cardamom),  £-2  fl.  oz. 

Aloes  is  also  contained  in  the  compound  extract  of  colocynth,  compound 
colocynth  pill,  pill  of  colocynth  and  hyoscyamus,  compound  gamboge  pill, 
compound  tincture  of  benzoin  and  compound  rhubarb  pill.  Some  of  the 
preparations  are  directed  to  be  made  from  Socotrine,  others  from  Barbadoes 
aloes,  but  there  is  really  no  difference  in  the  effects. 

U.  S.  P.— Frangula,  Buckthorn,  the  bark  of  Rhamnus  frangula,  collected 
at  least  one  year  before  being  used. 

Fluidextractum  Frangulce,  1—2  c.c.  (15—30  inins. ). 

U.  S.  P. — Rhamnus  Purshiana,  Cascara  sagrada,  the  bark  of  Rhamnus 
Purshiana. 

Extractum  Rhamni  Purshiance,  0. 25  G.  (4  grs. ). 

Fluidextractum  Rhamni  Purshiance  Aromaticum,  1  c.c.  (15  mins.). 

FLUIDEXTRACTUM  RHAMNI  PURSHIANCE,  1  c.c.  (15  mins.). 

B.  P. — Cascara  Sagrada,  the  dried  bark  of  Rhamnus  Purshianus. 

Extractum  Cascarce  /Sagradce,  2—8  grs. 

EXTRACTUM  CASCARA  SAGRADA  LIQUIDUM,  £-1  fl.  dr. 

Syrupus  Cascarce  Sagradce  Aromaticus,  ^—2  fl.  drs. 

Two  artificial  compounds  of  oxyanthraquinone  have  recently  been  introduced 
under  the  names  of  purgatin  and  exodin.  They  are  quite  insoluble  in  water  and 
tasteless  but  are  decomposed  in  the  intestine  and  act  there  like  the  other 
purgatives,  to  which  they  do  not  seem  superior.  Purgatin  colors  the  urine  red. 
Dose,  0.5-1.0  G.  (8-15  grs.),  in  friable  tablets  or  suspended  in  water. 

Of  these  numerous  preparations,  the  most  extensively  prescribed  are 
the  pills.  The  fluid  preparations  have  an  unpleasant,  bitter  taste,  and 
are  therefore  less  used,  unless  when  disguised  by  the  addition  of  sugar 
or  volatile  oils.  The  syrups  of  rhubarb  and  senna  are  often  admin- 
istered to  children,  and  the  confection  of  senna  and  the  compound 
liquorice  powder  are  also  pleasant,  easily  taken  preparations.  The 
compound  infusion  or  mixture  of  senna  and  the  compound  rhubarb 
powder  are  old  and  tried  preparations,  in  which  the  virtues  of  the 
vegetable  purgative  are  combined  with  those  of  a  saline  cathartic  and 
antacid  respectively ;  they  are  both  possessed  of  a  harsh,  unpleasant 
taste.  Frangula  is  comparatively  rarely  used,  but  the  fluid  extract  of 
cascara  sagrada,  which  is  practically  identical  with  it,  is  a  very  popular 
remedy  in  habitual  constipation. 

Pure  Chrysophanic  Acid  is  not  adapted  for  use  as  a  purgative,  as  even  in 
doses  of  0.3  G.  it  fails  to  increase  the  peristalsis.  A  compound  of  chryso- 
phanic  acid,  Chrysarobin  (C30H26O7),  has  found  employment  as  an  application 
in  some  forms  of  skin  disease,  especially  in  psoriasis,  in  which  it  is  often  of 
marked  benefit.  It  is  found  in  an  impure  form  (Goa  powder)  in  cavities  in 
the  Andira  araroba,  a  tree  growing  in  India  and  Brazil,  and  is  isolated  with 


VEGETABLE  PURGATIVES.  103 

comparative  ease  ;  it  forms  chrysophanic  acid  when  it  is  oxidized.  Chrysa- 
robin  is  much  more  irritant  than  chrysophanic  acid,  and  applied  to  the  skin 
in  a  concentrated  form,  or  in  susceptible  persons,  causes  itching,  redness  and 
swelling,  less  frequently  papular  or  pustular  eruptions  ;  the  skin  and  cloth- 
ing are  stained  a  reddish-brown  color  where  it  is  applied.  When  swallowed, 
chrysarobin  acts  as  a  gastro-intestinal  irritant,  causing  vomiting  and  purg- 
ing ;  some  of  it  is  absorbed,  and  in  its  excretion  by  the  kidneys  causes  in  the 
rabbit  nephritis  with  albumin  and  even  blood  in  the  urine.  In  man,  slight 
albuminuria  has  been  observed  in  some  instances  after  its  application  to  the 
skin  ;  in  animals  the  epithelium  of  the  renal  tubules  has  been  found  to  be 
necrosed,  the  glomeruli  being  less  frequently  affected.  It  was  anticipated 
that  it  would  undergo  oxidation  to  chrysophanic  acid  in  the  body,  and  this 
is  true  for  a  part  of  that  absorbed,  but  most  of  it  passes  through  the  tissues 
unchanged. 

Anthrarobin,  an  artificial  derivative  of  alizarin,  was  advised  at  one  time  as 
a  substitute  for  chrysarobin  and  chrysophanic  acid  in  the  treatment  of  psori- 
asis and  other  forms  of  skin  disease,  but  its  value  has  been  disputed  and  it  is 
comparatively  seldom  used  now.  Pyrogallol  apparently  acts  in  the  same 
way  in  psoriasis  as  chrysarobin,  and  the  effect  has  in  each  case  been  attrib- 
uted to  the  withdrawal  of  the  oxygen  from  the  diseased  skin. 

Araroba  (B.  P.),  or  Goa  powder,  a  substance  found  in  cavities  in  the  trunk 
of  Andira  araroba,  free  from  fragments  of  wood,  dried  and  powdered. 

Chrysarobinum  (B.  P.),  a  substance  obtained  from  Araroba  by  extracting 
with  hot  chloroform,  and  evaporating.  It  consists  for  the  most  part  of 
chrysarobin,  but  contains  some  chrysophanic  acid. 

Unguentum  Chrysarobini  (B.  P.),  4  per  cent. 

Chrysarobin  is  used  in  skin  diseases,  especially  in  psoriasis,  in  which 
it  is  applied  in  ointment.  Chrysophanic  acid  might  be  used  also  for 
this  purpose  were  its  isolation  not  attended  with  such  expense.  Some 
confusion  has  arisen  from  chrysarobin  having  been  at  first  supposed  to 
be  chrysophanic  acid. 

3.   The  Jalapin  and  Colocynthin  Group. 

The  third  group  of  the  vegetable  purgatives  comprises  a  number  of 
resinous  glucosides  and  acids,  whose  more  intimate  chemical  structure  is 
unknown,  though  a  number  of  them  appear  to  be  nearly  related  chemi- 
cally, so  that  it  is  possible  that  they  all  contain  a  common  radicle  like 
the  members  of  the  anthracene  group. 

Jalap  resin  contains  two  anhydride  glucosides,  Convolvulin  and  Jalapin,  the 
latter  only  in  very  small  quantity.  Scammony  consists  very  largely  of  Jala- 
pin.  Squirting  cucumber  contains  a  resin  (elaterium),  the  active  principle  of 
which  is  Elaterin,  another  anhydride  of  which  little  is  known.  Podophyl- 
lum  contains  two  isomeric  glucosides,  Podophyllotoxin  and  Picropodophyllin 
(C23H24O9).  Gamboge  owes  its  activity  to  Cambogic  acid,  which,  however,  is 
insoluble,  and  seldom  acts  unless  it  is  accompanied  by  the  inactive  bodies  of 
the  crude  drug.  Colocynthin  is  a  glucoside  occurring  in  the  colocynth  fruit, 
and  forms  Colocynthein  and  sugar  when  treated  with  acids.  Colocvnthein  is 
said  to  be  even  more  irritant  than  Colocynthin.  Bryony  contains  two  gluco- 
sides, Bryonin  and  Bryonidin,  of  which  the  latter  is  the  more  active.  Lep- 
tandra  owes  its  activity  to  a  resinous  glucoside,  Leptandrin,  euonymus  to  a 
glucoside,  Evonymin.  Many  other  plants  contain  similar  resinous  purgative 
substances,  and  some  of  these  are  used  as  remedies  to  some  extent,  but  so 
little  is  known  of  their  properties  and  they  are  so  seldom  employed  that  they 
may  be  omitted  here. 


104  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

Action. — These  substances  are  in  general  much  more  powerful  than 
any  of  the  other  purgatives  except  croton  oil,  and  are  therefore  classed 
along  with  the  latter  as  the  drastic  purgatives  or  hydragogue  cathar- 
tics. In  small  quantities  they  cause  evacuation  more  rapidly  than  the 
anthracene  purgatives,  and  in  somewhat  larger  doses  produce  profuse 
watery  stools  with  much  pain  and  often  tenesmus.  In  cases  of  poison- 
ing, the  bowel  undergoes  acute  inflammation,  and  blood  is  passed  in 
the  stools,  which  often  contain  shreds  of  epithelium  from  the  walls. 
The  irritant  action  is  not  confined  to  the  bowel  apparently  for  their 
administration  is  sometimes  followed  by  uneasiness  in  the  stomach, 
and  occasionally  by  nausea  and  vomiting.  On  the  other  hand,  mod- 
erate quantities  are  said  not  to  induce  colic  so  frequently  as  some  of 
the  anthracene  purges. 

Several  of  these  resinous  purges  are  irritant  to  the  skin  and  especially  to 
the  mucous  membranes  of  the  eye,  nose  and  throat.  Thus  jalap,  podophyl- 
lum  and  colocynthin  all  cause  pain  and  irritation  when  they  are  applied  to 
the  nostrils  in  fine  powder,  and  podophyllum  has  been  used  as  a  skin  irri- 
tant. 

The  presence  of  bile  in  the  intestine  increases  the  purgative  action  of  al- 
most all  these  bodies,  and  in  fact,  seems  absolutely  necessary  for  the  action 
of  most  of  them.  Some  of  them  induce  purgation  when  injected  hypodermically, 
and  this  effect  is  not  prevented  by  the  absence  of  bile  in  the  intestine. 

Podophyllotoxin  and  colocynthin  cause  purgation  when  injected  subcu- 
taneously  ;  this  is  probably  owing  to  their  excretion  into  the  bowel,  as  the 
former  has  been  detected  in  the  fa3ces  after  this  method  of  administration. 
Podophyllotoxin  causes  glomerular  nephritis  and  hemorrhages  into  various 
organs  when  administered  hypodermically  or  intravenously  in  large  quanti- 
ties, and  when  added  to  blood  in  a  test-tube,  it  causes  the  formation  of  met- 
ha3moglobin  in  the  corpuscles.  It  has  been  said  to  have  a  depressant  action 
on  the  central  nervous  system,  but  this  is  probably  a  result  of  the  shock  and 
hemorrhage  produced  by  its  intestinal  action.  Colocynthin  is  said  to  cause 
renal  inflammation  when  applied  subcutaneously  or  taken  internally,  and 
even  when  the  powder  is  inhaled  during  its  manufacture.  Jalapin  and  con- 
volvulin  given  by  the  mouth  cannot  be  found  in  the  faeces  or  urine,  and  are 
therefore  supposed  to  undergo  partial  or  complete  oxidation  in  the  body. 
Convolvulin  is  found  in  the  urine,  however,  when  it  is  injected  intraven- 
ously, and  no  purgation  follows  this  method  of  administration  ;  so  that  it  is 
probable  that  convolvulin  is  decomposed  in  the  bowel  when  it  is  adminis- 
tered internally. 

Euonymin  has  the  same  effect  on  the  heart  as  digitalis,  and  will  be  men- 
tioned along  with  it,  although  it  has  a  mild  purgative  action  and  is  used 
chiefly  as  an  aperient. 

PREPARATIONS. 

Colocynthis  (IT.  S.  P.),  colocynth,  the  fruit  of  Citrullus  Colocynthis  de- 
prived of  its  rind. 

Colocynthidis  Pulpa  (B.  P.),  the  dried  pulp  of  the  fruit  of  Citrullus  Colo- 
cynthis freed  from  seeds. 

Extractum  Colocynthidis  (U.  S.  P.),  0.1-0.3  G.  (2-5  grs.). 

EXTRA CTUM  COLOCYNTHIDIS  COMPOSITUM  (U.  S.  P.,  B.  P.)  (containing 
colocynth,  aloes,  scammony  and  cardamom),  0.2-1  G.  (3-15  grs.). 

Colocynthin,  5-10  mg.     (Not  pharmacopceial.) 


VEGETABLE  PURGATIVES.  105 

PILULE  CATHARTICS  COMPOSITE  (U.  S.  P.)  (compound  extract  of  colocynth, 
jalap,  gamboge  and  calomel),  I  pill  as  laxative ;  3  as  drastic  purgative. 

PILULE  CATHARTICS  YEGETABILES  (U.  S.  P.)  (contain  compound  extract 
of  colocynth,  jalap,  leptandra,  podophyllum,  hyoscyamus  and  oil  of  pepper- 
mint), 1  pill  as  laxative  ;  3  as  drastic  purgative. 

PILULA  COLOCYNTHIDIS  CoMPOSiTA  (B.  P.)  (colocynth,  Barbadoes  aloes, 
scammony  resin,  potassium  sulphate  and  oil  of  cloves),  4-8  grs. 

PILULA  COLOCYXTHIDIS  ET  HYOSCYAMI  (B.  P.),  (compound  pill  of  colo- 
cynth and  extract  of  hyoscyamus),  4-8  grs. 

Podophyllum  (U.  S.  P.)  Podophylli  Rhizoma  (B.  P.),  the  rhizome  and  roots 
of  Podophyllum  peltatum. 

Fluidextractum  Podophylli  (U.  S.  P.),  0.3-1  c.c.  (5-15  mins.). 

RESINA  PODOPHYLLI  (U.  S.  P.),  PODOPHYLLI  RESINA  (B.  P.),  15-60  nigs. 

tt-1  gr-). 

Pilulce  Podophylli,  Belladonnas  et  Capsici  (U.  S.  P.),  1  pill. 

TINCTURA  PODOPHYLLI  (B.  P.),  5-15  mins. 

Podophyllin  varies  considerably  in  composition,  and  ought  to  be  avoided. 

Podophyllotoxin.      5-10  mgs.     Neither  of  these  is  pharmacopeia! . 

Jalapa  (U.  S.  P.,  B.  P.),  the  tuberous  root  of  Ipomcea  Jalapa.  0.3-1  G. 
(5-15  grs.). 

Extractum  Jalapce  (B.  P.),  0.1-0.5  G.  (2-8  grs.). 

EESINA  JALAPS  (U.  S.P.),  JALAPS  RESINA  (B.  P.),  0.1-0.3 G.  (2-5  grs.). 

PULVIS  JALAPS  COMPOSITUS  (U.  S.  P.,  B.  P.)  contains  jalap  and  bitar- 
trate  of  potash.  1-4  G.  (15-60  grs.). 

Tinctura  Jalapse  (B.  P.),  i-1  fl.  dr. 

Scammonium  (U.  S.  P.),  a  resinous  exudation  from  the  living  root  of  Con- 
volvulus Scammonia. 

Resina  Scammonise  (U.  S.  P.),  0.2-0.5  G.  (3-8  grs.). 

B.  P. — Scammonise  Radix,  Scammony  root,  the  dried  root  of  Convolvulus 
Scammonia. 

Scammonium,  a  gum  resin  obtained  from  the  scammony  root,5-10  grs. 

Scammonise  Resina,  3-8  grs. 

PILULA  SCAMMONIS  COMPOSITA  (contains  jalap  and  ginger),  4-8  grs. 

Pulvis  Scammonii  Compositus  (contains  jalap  and  ginger),  10-20  grs. 

Scammony  is  also  contained  in  the  compound  colocynth  preparations. 

Euonymus  (U.  S.  P.),  Euonymi  Cortex  (B.  P.),  Wahoo,  the  dried  root- 
bark  of  Euonymus  atropurpureus. 

Extractum  Euonymi  (U.  S.  P.),  0.05-0.2  G.  (1-3  grs.). 

Extractum  Euonymi  Siccum  (B.  P.),  1-2  grs. 

Fluidextractum  Euonymi  (U.  S.  P.),  0.5  c.c.  (8  mins.). 

Elaterinum  (U.  S.  P.,  B.  P.),  C20H28O5,  a  neutral  principle  obtained  from 
elaterium,  a  substance  deposited  by  the  juice  of  the  fruit  of  Ecballium  Ela- 
terium  (squirting  cucumber).  1-5  mgs.  (fink  gr-)- 

Trituratio  Elaterini  (U.  S.  P.)  (one  part  elaterin  in  9  parts  sugar  of  milk), 
15-60  mgs.  (J-l  gr.). 

Elaterium  (B.  P.),  varies  in  strength,  ^-\  gr. 

Pulvis  Elaterini  Compositus  (B.  P.)  (one  part  elaterin  in  39  parts  milk 
sugar),  1-4  grs. 

Cambogia  (U.  S.  P.,  B.  P.),  Gamboge,  a  gum  resin  obtained  from  Garcinia 
Hanburii. 

Pilula  Cambogise  Composita  (B.  P.)  contains  Barbadoes  aloes  and  cinnamon, 
4-8  grs. 

Leptandra  (U.  S.  P.),  Culver's  root,  the  rhizome  and  roots  of  Veronica 
virginica. 

Extractum  Leptandra  (U.  S.  P.),  0.1-0.2  G.  (2-4  grs.). 

Fluidextractum  Leptandrce  (U.  S.  P.),  2-4  c.c.  (30-60  mins.). 


106  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

The  resinous  purgatives  are  generally  administered  in  pill  form  ; 
very  frequently  two  or  more  are  combined  in  one  pill,  or  they  may  be 
prescribed  along  with  extract  of  belladonna  or  hyoscyamus,  or  with  a 
drop  of  some  carminative  oil  or  resin,  to  prevent  the  pain  and  griping 
which  often  accompanies  their  action.  The  importance  of  these  purga- 
tives is  much  less  than  it  was  formerly,  and  several  of  them  are  very 
seldom  used ;  the  most  important  are  colocynth,  podophyllum,  and 
jalap.  In  large  doses  they  act  rapidly,  with  the  exception  of  podo- 
phyllum, which  induces  purgation  very  slowly  (10-20  hours). 

Therapeutic  Uses  of  the  Purgatives.  —  The  purgatives  are  employed 
to  cause  evacuation  of  the  bowel  when  for  any  reason  its  peristalsis  is 
slow.  In  ordinary  constipation  of  short  standing,  in  which  the  peri- 
stalsis may  merely  seem  somewhat  more  sluggish  than  usual,  the  milder 
laxatives  are  prescribed — castor  oil,  senna,  rhubarb,  aloes,  frangula,  or 
cascara  sagrada.  The  first  two  cause  least  disturbance  of  the  bowel, 
but  are  disagreeable  to  take,  and  are  less  commonly  prescribed  for 
adults  than  rhubarb  or  cascara,  or  small  doses  of  colocynth  or  podo- 
phyllum. In  children  or  in  debility  in  adults,  senna  and  castor  oil 
are  frequently  used  however. 

In  chronic  constipation  which  cannot  be  controlled  by  hygienic 
measures,  or  by  the  use  of  a  special  dietary  such  as  fruits,  or  coarse 
meal,  and  where  the  intestine  has  apparently  taken  on  a  sluggish  habit, 
rhubarb,  cascara,  aloes,  podophyllum,  or  colocynth  may  be  ordered, 
but  the  saline  cathartics  often  prove  more  satisfactory.  Khubarb  tends 
to  cause  some  constipation  after  its  laxative  effects,  but  is  often  used  in 
these  cases,  as  it  possesses  some  bitter  stomachic  action,  which  compen- 
sates for  its  astringent  after-effects.  This  bitter  action  is  often  given 
to  the  other  purgatives  by  the  addition  of  gentian,  nux  vomica,  or 
cinchona.  In  obstinate  constipation,  in  which  the  bowel  contains  hard 
faecal  masses,  the  milder  purgatives  often  provoke  griping  without 
relieving  the  condition,  and  in  these  cases  larger  doses  of  colocynth, 
jalap,  podophyllum,  or  croton  oil  are  used,  along  with  some  of  the  ex- 
tracts of  the  atropine  group  or  with  a  carminative  oil.  They  may  be 
prescribed  along  with  some  of  the  saline  cathartics,  as  in  the  compound 
infusion  of  senna  or  the  compound  powder  of  jalap. 

Croton  oil  is  used  especially  where  the  drug  is  required  to  be  of 
small  bulk  and  the  administration  is  attended  with  special  difficulty ; 
thus  in  unconsciousness  or  mania  one  or  two  drops  may  be  given  on 
sugar.  In  lead  colic,  croton  oil  is  said  to  act  more  rapidly  and  effi- 
ciently than  the  others. 

In  some  forms  of  diarrhoea  constant  irritation  seems  to  be  kept  up 
by  the  presence  of  irritants  in  the  bowel,  and  the  indications  are  the 
removal  of  these  by  a  purge  rather  than  the  administration  of  astrin- 
gents. Castor  oil,  senna,  and  rhubarb  are  especially  adapted  for  this 
purpose ;  the  two  first  because  they  increase  the  irritation  of  the  bowel 
less  than  the  others,  the  latter  because  of  its  subsequent  astringent 
action. 


VEGETABLE  PURGATIVES.  107 

A  purgative  is  often  administered  as  a  preliminary  in  the  treatment 
of  malaria,  syphilis  and  other  conditions,  and  seems  to  have  beneficial 
effects,  although  these  are  difficult  to  explain.  In  the  beginning  of 
acute  fevers  also  a  purge  is  often  useful,  perhaps  through  the  conges- 
tion of  the  bowel  withdrawing  the  blood  from  the  rest  of  the  body,  or 
through  the  removal  of  poisonous  substances  formed  by  the  decompo- 
sition of  the  intestinal  contents.  In  congestion  of  the  brain  a  purga- 
tive is  often  administered  with  good  effects,  which  may  also  be  attributed 
to  the  accumulation  of  blood  in  the  mesenteric  circulation,  and  perhaps 
to  some  action  analogous  to  counter-irritation  of  the  skin.  For  these 
purposes  a  sharp  purge  is  generally  used,  either  croton  oil  or  one  of 
the  jalapin  and  colocynthin  series. 

The  more  powerful  purgatives  were  formerly  largely  used  to  remove 
fluid  from  the  body  in  cases  of  dropsy  or  oedema,  and  they  were  gener- 
ally prescribed  along  with  the  saline  cathartics  for  this  purpose.  The 
violent  action  required  is  weakening,  however,  and  while  the  fluid  is 
withdrawn  to  a  greater  or  less  extent,  the  condition  of  the  patient  often 
undergoes  little  improvement,  so  that  this  measure  is  comparatively 
seldom  used  now. 

The  congestion  of  the  pelvic  organs  induced  by  these  purges  is  not 
infrequently  beneficial  in  cases  of  amenorrhoea.  Aloes  is  almost  exclu- 
sively used  for  this  purpose,  and  is  generally  administered  along  with 
iron  or  with  myrrh,  which  is  credited  with  some  special  action  on  the 
genital  organs. 

The  purges  act  as  intestinal  disinfectants  by  removing  the  micro- 
organisms mechanically,  though  the  vegetable  purges  are  less  used 
for  this  purpose  than  calomel.  A  purgative  is  administered  to  remove 
poisons  in  the  intestine  when  they  have  passed  beyond  the  stomach 
or  when  they  are  excreted  into  the  bowel. 

Purgatives  are  contraindicated  in  conditions  of  acute  intestinal  irri- 
tation, and  during  menstruation  and  pregnancy,  owing  to  the  conges- 
tion of  the  pelvic  organs,  which  may  lead  to  an  excessive  flow  in  the 
one  case  and  to  abortion  in  the  other ;  aloes  is  especially  dangerous 
in  these  conditions.  In  collapse,  asthenia  and  anemia,  powerful  pur- 
gatives are  contraindicated,  owing  to  the  irritation  they  produce. 
In  hemorrhoids,  aloes  is  often  said  to  do  harm  by  increasing  the  con- 
gestion of  the  rectum,  and  powerful  purges  are  injurious  from  the 
straining  they  cause,  but  if  constipation  is  present,  a  mild  purgative  is 
beneficial.  In  all  those  conditions,  if  a  purgative  is  required,  either 
castor  oil,  senna  or  rhubarb  ought  to  be  chosen. 

Eepeated  attempts  have  been  made  to  produce  evacuation  of  the  howels 
by  substances  injected  subcutaneously.  Hiller  found  colocynthin  the  best 
available  for  practical  purposes,  although  aloin  and  cathartinic  acid  also 
acted  efficiently.  The  injection  is  so  painful,  however,  that  it  ought  only  to 
be  had  recourse  to  in  exceptional  circumstances.  Dixon  has  recently  suggested 
the  use  of  apocodeine  for  this  purpose  (see  Apomorphine). 

Another  method  by  which  the  purgatives  may  be  administered  is  in  enema. 


108  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

The  addition  of  purgatives,  such  as  castor  oil,  and  of  bile  to  the  ordinary 
enemata  has  been  practised  for  many  years,  but  Kohlstock  has  recently 
drawn  attention  to  the  use  of  purgatives  by  enema  with  only  1-3  teaspoonfuls 
of  fluid.  The  large  water  enema,  containing  a  pint  or  more  of  fluid,  acts 
mainly  by  distending  the  bowel  and  thus  setting  up  peristalsis,  although  the 
soaps,  salt  and  other  similar  bodies,  which  are  often  added  to  it,  may  have 
an  irritating  effect  in  addition.  In  the  small  enema,  however,  distention 
plays  no  part,  the  movement  being  elicited  by  the  irritant  action  of  the  drug. 
Kohlstock  found  that  colocynthin  (0.01-0.03  G.),  aloin  (0.4-0.5  G.),  and 
cathartinic  acid  (0.6  G.)  dissolved  in  glycerin  caused  purgation,  colocynthin 
acting  in  £-2  hrs.,  aloin  in  2-12  hrs.  and  cathartinic  acid  in  1-6  hrs.  The 
two  latter  were  certain  in  their  effects  only  in  cases  of  moderate  constipation. 
He  attributes  their  action  to  absorption  from  the  rectum. 

BIBLIOGRAPHY  OF  THE  VEGETABLE  PURGATIVES. 
Purgative  action  in  general. 

Brunton.     Practitioner,  xii.,  p.  342. 

Siadelmann.     Berliner  klin.  Woch.,  1896,  p.  181.     Archiv  f.  exp.  Path.  u.  Pharm., 
xxxvii.,  p.  352. 

Wood.     Amer.  Journ.  of  Med.  Sciences,  lx.,  p.  75. 

Hitter.    Ztschr.  f.  klin.  Med.,  iv.,  p.  481. 

Kohlstock.     Charite-annalen,  xvii.,  p.  283. 

Magnus.     Ergebnisse  der  Physiologic,  ii.  (2),  p.  661     (Literature.) 

Tappeiner.     Arch,  internat.  de  Pharmacodyn,  x.,  p.  80. 

Dixon.     Brit.  Med.  Journ.,  Oct.  18,  1902. 

Purgative  oils. 

Buchheim.     1.  c. 

Meyer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxviii.,  p.  145  ;  xxxviii.,  p.  336. 

Robert  u.  Hirschheydt.     Arb.  des  pharmak.  Institutes  zu  Dorpat,  iv.,  p.  5. 

Anthracene  purgatives. 

ALOIN.     Meyer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxviii.,  p.  186. 
Kohn.     Berl.  klin.  Woch.,  1882,  p.  68. 
Murset.     Archiv  f.  exp.  Path.  u.  Pharm.,  xix.,  p.  310. 
Esselmont.     Ibid.,  xliiL,  p.  274. 

Tschirch.     Bericht.  d.  deutsch.  pharmaceut.  Gesellsch.,  1898,  p.  174. 
SENNA.     Kubly.     Inaug.  Diss.,  Dorpat,  1865. 
Stockman.     Arch.  f.  exp.  Path.  u.  Pharm.,  xix.,  p.  117. 
Gensz.     Inaug.  Diss.,  Dorpat,  1893. 
Vieth.     Munch,  med.  Woch.,  1901,  No.  35. 
FRANGULA.     Baeumker.     Inaug.  Diss.,  Gottingen,  1880. 

CHRYSAROBIN  AND  ANTHRAROBIN.      Lewin  u.  Eosenthal     Virch.  Arch.,  Ixxxv., 
p.  118. 

Midler.     Munch,  med.  Woch.,  1896,  p.  1221. 

Weyl.     Pfliiger's  Arch.,  xliii.,  p.  367. 

Koch.     Inaug.  Diss.,  Giessen,  1880. 

Marshall.     Scottish  Med.  and  Surg.  Journ.,  May,  1902.     (Purgatin.) 

Ebstein.     Deutsch.  med.  Woch.,  1904,  p.  12.     (Exodin..) 

Jalapin  and  Colocynthin  Series. 

PODOPHYLLUM.     Podwyssotzki.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiii.,  p.  29. 
Neuberger.     Ibid.,  xxviii.,  p.  32. 
Kiirsten.     Archiv  der  Pharm.,  ccxxix.,  p.  220.        ;;, 
Spindler.     Inaug.  Diss.,  Dorpat,  1893. 
JALAP.     J.  Muller.     Inaug.  Diss.,  Dorpat,  1885. 

Scher.     Inaug.  Diss.,  Dorpat,  1895  ;  Virchow-Hirsch  Janresber.,  1895,  p.  380. 
COLOCYNTH.     Hagentorn.     Inaug.  Diss.,  Dorpat,  1857. 
ELATERIUM.     Kb'hler.     Virch.  Arch.,  xlix.,  p.  408. 

BRYONIA.     Mankowsky.     Historische  Studien  a.  d.  pharmakol.  Instit.,  Dorpat,  ii., 
p.  143. 


VEGETABLE  ASTRINGENTS —TANNIC  ACID  SERIES.         109 

VII.   VEGETABLE  ASTRINGENTS  — TANNIO  ACID  SERIES. 

A  large  number  of  vegetable  substances  owe  their  action  to  their 
containing  tannin  substances,  while  in  many  other  preparations  the  ef- 
fect of  more  important  constituents  is  modified  by  the  presence  of 
these  widely  distributed  bodies.  Tannic  acid  proper  is  derived  from 
the  oak  gall,  and  seems  to  consist  of  an  anhydride  combination  of 
gallic  acid,  into  which  it  is  very  easily  decomposed,  probably  according 
to  the  following  equation  : 

Tannic  acid.  Gallic  acid. 

C6H2(OH)3CO  — 0(OH)2C6H2COOH  +  H20^2C6H2(OH3)COOH. 

Gallic  acid  is  formed  from  a  large  number  of  other  bodies  which 
closely  resemble  tannic  acid  in  their  general  features,  but  are  by  no 
means  identical  with  it.  Their  constitution  is  altogether  unknown, 
but  they  possess  a  number  of  reactions  in  common  and  are  generally 
classed  together  as  the  tannic  acid  substances.  Some  of  them  contain 
a  sugar,  and  tannin  or  tannic  acid  is  therefore  sometimes  said  to  be  a 
glucoside.  These  bodies  precipitate  albumins,  gelatins,  alkaloids  and 
some  glucosides,  and  the  salts  of  the  heavy  metals.  The  salts  of  iron 
form  a  bluish-black  or  greenish-black  precipitate,  and  an  attempt  is 
sometimes  made  to  divide  the  forms  of  tannic  acid  by  this  reaction, 
but  they  may  be  better  indicated  by  their  origin,  as  kinotannic  acid 
from  kino,  catechutannic  acid  from  catechu,  etc. 

Action.  —  The  pharmacological  effects  of  these  bodies  are  due  to 
their  precipitating  albumins  and  other  proteids,  and 'this  reaction 
may  therefore  be  described  before  their  action  in  the  body.  If 
tannic  acid  solution  be  added  to  a  neutral  solution  of  albumin  or 
gelatin,  a  white  precipitate  falls,  which  is  entirely  insoluble  in  water, 
but  is  soluble  in  excess  of  albumin  or  gelatin,  in  acetic  or  lactic  acid, 
and  in  alkaline  solutions.1  Solutions  of  pepsin  and  of  peptones  are  also 
precipitated  by  tannic  acid  unless  in  the  presence  of  an  acid.  If  pro- 
teid  tannate  be  exposed  to  the  action  of  the  gastric  juice  it  undergoes 
digestion  and  is  dissolved  in  the  same  way  as  an  ordinary  coagulated 
proteid  such  as  fibrin.  During  the  process  the  tannic  acid  is  set  free 
from  its  combination  apparently,  and  can  precipitate  undigested  pro- 
teids, although  it  has  no  effect  on  the  peptones  in  the  acid  medium. 
When  a  soluble  tannate  is  formed  by  the  addition  of  soda  or  potash  to 
a  tannic  acid  solution,  the  presence  of  proteids  produces  no  precipitate, 
the  affinities  of  the  acid  being  satisfied  by  the  alkali,  and  for  the  same 
reason  the  tannic  acid  precipitate  is  dissolved  in  the  presence  of 
alkalies. 

Tannic  acid  applied  to  animal  tissue,  as  in  the  tanning  of  leather, 
causes  a  precipitation  of  the  proteids,  and  the  tissue  becomes  harder 
and  tougher  and  tends  to  shrink  together  ;  at  the  same  time  it  has  less 
tendency  to  undergo  putrefactive  changes  and  does  not  lose  its  flexi- 

1  Some  discrepancies  in  the  accounts  of  different  authors  in  regard  to  these  reactions 
are  perhaps  due  to  variations  in  the  amount  of  the  neutral  salts  in  their  preparations. 
The  account  given  by  Lewin  has  been  followed  in  the  text. 


110  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

bility,  as  it  would  in  drying.  Strong  solutions  cause  an  immediate 
dense  precipitate  of  the  proteids  on  the  surface  and  prevent  the  further 
penetration  of  the  coagulating  fluid,  while  the  more  dilute  solutions  are 
believed  to  penetrate  more  deeply  and  thus  to  cause  a  more  complete 
precipitation  of  the  proteids  of  the  tissue. 

Tannic  acid  solutions  have  a  harsh,  bitter,  "astringent"  taste  and 
produce  in  the  mouth  a  feeling  of  constriction,  dryness  and  rough- 
ness, along  with  a  sense  of  stiffness  in  the  movements  of  the  tongue, 
and  some  loss  of  taste.  These  effects  are  due  to  the  coagulation  of  the 
superficial  layers  of  proteid  both  within  and  without  the  epithelium, 
which  substitutes  for  the  ordinary  smooth  surface  a  firmer,  less  even 
one,  over  which  the  tongue  can  no  longer  move  easily.  The  feeling 
of  constriction  may,  perhaps,  be  caused  by  an  actual  shrinking  of  the 
superficial  layers  of  the  epithelium,  or  may  be  due  merely  to  the  im- 
paired movements  and  sensation. 

The  astringent  feeling  is  continued  in  the  throat  as  the  solution  is 
swallowed,  and  occasionally  some  discomfort  or  even  nausea  and  vomit- 
ing are  provoked  by  it,  but  as  a  general  rule  no  such  effects  are  observed. 
The  stools  are  rendered  harder  and  firmer  by  the  administration  of 
tannic  acid,  and  constipation  is  often  produced  by  it.  In  excess,  tannic 
acid  sometimes  causes  irritation  of  the  intestine  and  diarrhoea,  but 
beyond  these  symptoms  of  local  irritation  of  the  stomach  and  bowel, 
no  effects  arise  from  even  enormous  quantities  of  the  drug. 

In  the  stomach,  tannic  acid  combines  with  any  proteid  substance  with 
which  it  may  -come  in  contact  and  precipitates  it,  but  as  digestion  pro- 
gresses, this  combination  is  broken  up,  as  the  peptones  do  not  combine 
with  tannic  acid  in  acid  solution,  and  the  astringent  action  is  therefore 
exercised  on  the  walls  of  the  stomach  and  intestine.  Ordinary  quanti- 
ties cause  the  same  superficial  coagulation  as  in  the  mouth,  but  if  large 
doses  be  given  when  the  stomach  and  intestine  are  not  protected  by 
foodstuffs,  a  more  complete  coagulation  of  the  mucous  membrane  takes 
place  and  the  consequent  irritation  results  in  vomiting,  and  sometimes 
in  diarrhoea.  The  increase  in  the  consistency  of  the  stools  is  probably 
due  to  the  layer  of  coagulated  proteid  acting  as  a  protective  to  the 
bowel,  lessening  its  irritability  and  thus  retarding  its  movements,  so 
that  there  is  longer  time  for  the  absorption  of  the  fluid  part  of  its 
contents,  although  this  proceeds  more  slowly  under  tannic  acid  than 
normally  (Gebhardt).  Yeasts  and  microbes  are  precipitated  by  tannin, 
and  this  may  tend  to  lessen  the  fermentations  in  the  bowel  in  some 
cases,  although  some  preparations  of  tannic  acid  which  have  been  ex- 
amined in  regard  to  this  point  have  been  found  to  have  little  or  no 
effect  on  intestinal  putrefaction. 

The  local  application  of  tannic  acid  causes  a  diminution  of  the  se- 
cretions of  glands,  as  has  been  demonstrated  by  Schutz.  This  is  due 
to  its  effects  upon  the  protoplasm  of  the  secreting  cells,  which  probably 
undergo  the  initial  stages  of  coagulation. 

It  was  formerly  believed  that  tannic  acid  caused  constriction  of  the 
vessels  of  any  part  to  which  it  was  applied,  but  some  doubt  has  been 


VEGETABLE  ASTRINGENTS—  TANNIG  ACID  SERIES.         Ill 

thrown  on  this  by  the  experimental  results  obtained  by  Roseustirn  and 
others.  Heinz,  the  most  recent  writer  on  the  subject,  found  that 
solutions  of  tannic  acid  of  less  strength  than  J  per  cent,  caused  con- 
striction of  the  meseuteric  vessels  of  the  frog  or  rabbit  when  applied 
directly,  while  more  concentrated  solutions  caused  transient  constric- 
tion followed  by  dilation.  Another  local  effect  produced  by  tannic 
acid  is  seen  in  the  cessation  of  the  movements  of  the  leucocytes  in  the 
tissues  around  the  point  of  application  and  the  arrest  of  their  diapedesis 
through  the  walls  of  the  vessels. 

When  tannic  acid  comes  in  contact  with  blood  in  a  test-tube  it  pre- 
cipitates the  albumins,  and  when  it  is  injected  intravenously,  the  precip- 
itate formed  leads  to  the  formation  of  emboli.  The  alkaline  tannates 
are  generally  believed  to  be  entirely  devoid  of  astringent  effects,  unless 
when  the  tannic  acid  is  freed  from  the  combination  by  the  presence  of 
an  acid,  but  according  to  Heinz  and  Gottlieb  the  astringent  action  is 
only  weakened  and  not  entirely  removed  by  combination  with  the 
alkalies. 

The  fate  of  tannic  acid  in  the  body  has  given  rise  to  some  discussion. 
When  it  is  taken  internally  a  small  proportion  is  sometimes  eliminated 
by  the  bowel  unchanged,  but  very  often  none  is  to  be  found  in  the 
stools ;  traces  are  apparently  absorbed  and  excreted  in  the  urine  as  so- 
dium tannate  in  both  man  and  animals,  although  some  investigators 
have  failed  to  detect  these.  When  sodium  tannate  is  administered  in- 
ternally, a  distinctly  larger  amount  of  it  is  absorbed  and  reappears  in 
the  urine.  But  much  the  greater  part  of  the  tannic  acid  is  decomposed 
in  the  intestine  into  gallic  acid,  some  of  which  often  passes  out  in  the 
stools,  some  in  the  urine.  Only  about  one  per  cent,  of  the  tannic  acid 
swallowed  reappears  in  the  excretions,  either  as  tannic  or  gallic  acid ; 
the  rest  apparently  undergoes  complete  oxidation  in  the  tissues,  for  no 
further  trace  of  it  can  be  found.  After  tannic  acid  is  administered, 
some  tannic  or  gallic  salt  is  present  in  the  blood,- for  iron  salts  give  a 
darker  color  to  it,  but  it  is  impossible  to  state  whether  this  is  tannin 
or  a  gallate,  although  in  all  probability  it  is  the  latter.  According  to 
Harnack,  the  gallic  acid  in  the  urine  sometimes  forms  pyrogallol  on 
standing,  but  this  poisonous  substance  is  not  formed  from  tannic  acid 
in  the  intestine  or  tissues. 

Tannic  acid  then  does  not  exist  in  the  tissues  as  such,  but  only  in 
the  form  of  traces  of  the  gallate  or  tannate  of  soda,  which  are  so  small 
as  to  be  devoid  of  astringent  properties.  Tannate  of  soda  seems  to 
have  no  action  whatever,  while  gallic  acid  has  no  further  properties 
than  other  weak  acids.  Theoretically,  therefore,  it  is  to  be  expected 
that  the  effects  of  tannic  acid  are  limited  to  the  point  of  application, 
and  there  is  no  evidence  of  any  weight  that  it  exercises  any  action  after 
absorption. 

Lewin  states  that  the  muscles  of  the  frog  are  altered  in  elasticity  after  the 
application  of  tannic  acid  subcutaneously,  and  an  old  observation  is  recorded 
in  which  the  spleen  was  supposed  to  undergo  contraction  when  tannic  acid 
was  administered,  but  the  methods  adopted  render  these  observations  worth- 


112  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

less.  Tannic  acid  is  often  said  to  lessen  the  albuminuria  in  certain  forms  of 
Bright' s  disease,  but  the  only  exact  determinations  which  have  been  made 
in  man  showed  that  no  such  effect  was  present,  and  in  Ribberts'  experiments 
the  animals  were  moribund  when  the  improvement  occurred,  and  no  safe 
deductions  can  be  made  therefore.  The  urine  is  sometimes  said  to  be 
diminished  by  tannic  acid,  but  this  statement  is  based  on  error.  Last  of 
all,  tannic  acid  is  said  to  lessen  internal  hemorrhage  by  contracting  the 
vessels,  but  tannate  of  soda,  the  only  form  in  which  it  can  exist  in  the  blood 
is  entirely  devoid  of  action. 

Gallic  acid  given  by  the  mouth  is  absorbed  and  is  excreted  by  the  kidneys 
to  some  extent.  Much  of  it  disappears  in  the  tissues,  however,  apparently 
by  oxidation.  The  excretion  of  uric  acid  in  the  urine  is  considerably  reduced 
by  the  administration  of  gallic  acid. 

The  numerous  preparations  of  the  pharmacopoeias  which  owe  their 
activity  to  their  containing  tannic  acid,  differ  from  the  pure  drug  in  that 
the  acid  is  only  slowly  dissolved  out  from  the  colloid  mass,  and  there- 
fore acts  less  on  the  stomach  and  affects  a  greater  length  of  intestine. 

PREPARATIONS. 

Acidum  Tannicum  (IT.  S.  P.,  B.  P.),  tannic  acid,  gallotannic  acid  or  digallic 
acid  (HC14H9O9),  an  organic  acid  obtained  from  nut  gall,  0.1-0.6  G.  (2-10 
grs.). 

GLYCERITUM  ACIDI  TANNICI  (U.  S.  P.),  GLYCERINUM  ACIDI  TANNICI 
(B.  P.). 

Unguentum  Acidi  Tannici  (U.  S.  P.). 

Collodium  Stypticum  (U.  S.  P.). 

Trochisci  Acidi  Tannici  (U.  S.  P.),  0.06  G.  (1  gr.)  ;  (B.  P.),  J  gr.  in  ea'ch. 

Suppositoria  Acidi  Tannici  (B.  P.),  0.2  G.  (3  grs.)  in  each. 

Acidum  Gallicum  (U.  S.  P.,  B.  P.),  gallic  acid  (HC7H5O5),  an  organic  acid 
usually  prepared  from  tannic  acid,  has  no  astringent  properties,  nor,  in  fact 
any  qualities  which  render  it  of  value  in  medicine. 

GAMBIR  (U.  S.  P.),  an  extract  prepared  from  the  wood  of  Ourouparia  Gambir, 
1G.  (15  grs.). 

TINCTURA  GAMBIR  COMPOSITA  (U.  S.  P.),  (flavored  with  cinnamon),  4  c.c.  (1 
fl.  dr.). 

Trochisci  Gambir  (U.  S.  P.). 

Gambir  has  been  substituted  for  the  Catechu  of  former  editions  of  the  Pharma- 
copoeia. 

Catechu  (B.  P.),  an  extract  of  the  leaves  and  young  shoots  of  Uncaria 
Gambier. 

TINCTURA  CATECHU,  $-1  fl.  dr. 

Trochisci  Catechu,  each  containing  0.065  G.  (1  gr.)  of  catechu. 

Pulvis  Catechu  Compositus  contains  catechu,  kino,  krameria,  cinnamon  and 
nutmeg,  10-40  grs. 

Krameria  (U.  S.  P.),  Ehatany,  the  root  of  Krameria  triandra  and  of 
Krameria  Ixina,  Kramerise  Radix  (B.  P.),  the  dried  root  of  Para  Ehatany 
(Krameria  argentea  ?)  or  of  Peruvian  Rhatany  (Krameria  triandra). 

EXTRACTUM  KRAMERIA  (U.  S.  P.,  B.  P.),  0.3-1  G.  (5-15  grs.). 

Fluidextractum  Kramerice  (U.  S.  P.),  0.5-4  c.c.  (10-60  mins.). 

Tinctura  Kramerise  (U.  S.  P.,  B.  P.),  2-8  c.c.  (J-2  fl.  drs.). 

Syrupus  Kramerise  (U.  S.  P.),  2-10  c.c.  Q-3  fl.  drs.). 

Liquor  Kramerise  Concentratus  (B.  P.),  £-1  fl.  dr. 

Infusum  Kramerise  (B.  P.),  J-l  fl.  oz. 

Trochisci  Krameriae  (U.  S.  P.,  B.  P.). 

Trochiscus  Kramerise.  et  Cocainse  (B.  P.),  each  containing  ^  gr.  of  cocaine. 


VEGETABLE  ASTRINGENTS— T ANN  1C  ACID  SERIES.         113 

Kino  (U.  S.  P.,  B.  P.),  the  inspissated  juice  of  Pterocarpus  Marsupium, 
0.5-2  G.  (10-30  grs.). 

TINCTURA  KINO  (U.  S.  P.,  B.  P.),  2-8  c.c.  (J-2  fl.  drs.). 

PULVIS  KINO  COMPOSITUS  (B.  P.),  contains  5  per  cent,  of  opium,  5-20  grs. 

Hamamelidis  Folia  (U.  S.  P.,  B.  P.),  Witchhazel,  the  leaves  of  Hamamelis 
Virginiana,  contains  tannic  acid,  a  volatile  oil  and  a  bitter. 

Hamamelidis  Cortex  (U.  S.  P.,  B.  P.),  the  dried  bark  of  Hamamelis  Virgin- 
iana, witchhazel  bark. 

Fluidextractum  Hamamelidis  Foliorum  (U.  S.  P.),  2  c.c.  (30  mins.). 

Aqua  Hamamelidis  (U.  S.  P.),  8  c.c.  (2  fl.  drs.). 

Extractum  Hamamelidis  Liquidum  (B.  P.),  5-15  mins. 

Liquor  Hamamelidis  (B.  P.). 

Tinctura  Hamamelidis  (B.  P.),  J-l  fl.  dr. 

Unguentum  Hamamelidis  (B.  P.). 

Haematoxylon  (U.  S.  P.),  Haematoxyli  Lignum  (B:  P.),  Logwood,  the 
heart-wood  of  Hsematoxylon  campechianum. 

Extractum  Hsematoxyli  (U.  S.  P.),  0.5-2  G.  (10-30  grs.). 

Decoctum  Hsematoxyli  (B.  P.),  £-2  fl.  oz. 

Eucalypti  G-ummi  (B.  P.),  a  ruby-colored  exudation,  or  so-called  red  gum, 
from  the  bark  of  Eucalyptus  rostrata  and  some  other  species  of  Eucalyptus. 
2-5  grs. 

Trochiscus  Eucalypti  Gummi  (B.  P.),  each  containing  1  gr.  of  the  gum. 

Geranium  (U.  S.  P.),  Cranesbill,  the  rhizome  of  Geranium  maculatum. 
1-2  G.  (15-30  grs.). 

Fluidextractum  Geranii  (U.  S.  P.),  2-4  c.c.  (30-60  mins.). 

Rubus  (U.  S.  P.),  Blackberry,  the  bark  of  the  root  of  Kubus  villosus,  R. 
Canadensis  and  R.  trivialis. 

Fluidextractum  Rubi  (U.  S.  P.),  2-8  c.c.  (J-2  fl.  drs.). 

Syrupus  Rubi  (U.  S.  P.),  2-8  c.c.  (£-2  fl.  drs.). 

Galla  (U.  S.  P.,  B.  P.),  Nut-gall,  an  excrescence  on  Quercus  lusitonica 
(Quercus  infectoria,  B.  P.),  one  of  the  oaks,  caused  by  the  punctures  and 
ova  of  an  insect,  Cynips  Galla3  tinctorise. 

Tinctura  Gallve  (U.  S.  P.),  2-12  c.c. 

Unguentum  Gallte  (U.  S.  P.,  B.  P.). 

Unguentum  Gallse  cum  Opio  (B.  P.)  contains  7J  per  cent,  of  opium. 

Quercus  (U.  S.  P.),  white  oak  bark.     1  G.  (15  grs.). 

Fluidextractum  Quercus  (U.  S.  P.),  1  c.c.  (15  mins.). 

Rhus  glabra  (U.  S.  P.),  the  fruit  of  sumach. 

Fluidextractum  Rhois  Glabrce  (U.  S.  P.). 

Several  new  preparations  of  tannic  acid  have  been  introduced  into  thera- 
peutics of  late  years,  chiefly  for  use  as  intestinal  astringents.  Tannic  acid 
itself  is  liable  to  produce  irritation  of  the  stomach,  and  to  be  decom- 
posed or  absorbed  to  a  large  extent  before  it  reaches  the  large  intestine,  and 
although  the  cruder  preparations  are  less  liable  to  these  changes,  even  they  are 
by  no  means  devoid  of  disagreeable  features.  Meyer,  therefore,  introduced 
tannigen,  or  diacetyltannin,  in  which  two  of  the  original  hydroxyl  groups  of 
the  tannic  acid  are  replaced  by  acetyl.  This  body  is  exceedingly  insoluble  in 
Avater,  but  is  dissolved  by  alkalies.  It  was  hoped  that  it  would  remain  insol- 
uble in  the  stomach  and  only  commence  to  act  in  the  bowel,  and  Rost  finds 
that  after  administration  by  the  mouth,  it  occurs  in  the  human  faeces  in  small 
quantity  as  tannic  acid,  while  in  the  cat  it  passes  through  the  alimentary 
canal  in  part  unchanged.  At  the  same  time  the  presence  of  gallic  acid  in  the 
urine  indicates  that  part  of  it  undergoes  the  fate  of  tannic  acid.  Tannoform 
is  a  somewhat  similar  combination  of  tannic  acid  and  formaldehyde,  while 
tannopin  is  a  still  more  recent  and  untried  member  of  the  series.  Both 
tannigen  and  tannoform  are  astringent  in  the  mouth  and  stomach,  but  reach 
the  bowel  owing  to  their  insolubility.  The  tannalbin  of  Gottleib,  on  the 
other  hand,  is  a  combination  of  tannic  acid  and  albumen,  dried  at  such  a 


114  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

temperature  as  to  prevent  the  action  of  the  gastric  juice  upon  it,  but  capable 
of  being  broken  up  by  the  more  powerful  pancreatic  fluids.  It  is  entirely 
insoluble  and  is  not  astringent  until  digested  in  the  bowel,  so  that  it  has  no 
irritant  action  on  the  stomach  and  is  tasteless.  Host  found  tannalbin  and 
tannic  acid  in  the  fa3ces  of  the  cat  after  its  administration,  while  only  gallic 
acid  occurs  in  the  stools  and  urine  in  man,  showing  that  in  the  latter  the 
whole  of  the  tannalbin  administered  is  decomposed  in  its  passage  through 
the  alimentary  canal.  Tannocol  is  a  combination  of  tannic  acid  and  gelatin, 
resembling  tannalbin  in  most  respects. 

TANNIGEN,  0.5-2  G.  (10-30  grs.),  in  powder. 
TANNALBIN,  0.5-2  G.  (10-30  grs.),  in  powder. 

Several  combinations  of  gallic  acid  have  been  introduced  of  late  years  as 
astringents.  They  can  have  no  such  effect,  however,  and  must  be  regarded 
as  additions  to  the  group  of  inert  protective  powders,  which  is  already  rep- 
resented in  overabundance  in  therapeutics. 

Therapeutic  Uses. —  The  preparations  of  tannic  acid  ought  to  be  used 
for  their  local  effects  exclusively.  They  are  applied  externally  in 
cases  of  excessive  secretion,  as  in  local  sweating  or  weeping  ulcers,  and 
occasionally  to  harden  the  skin.  For  this  purpose  tannic  acid  may  be 
used  in  solution  in  water,  or  in  the  form  of  the  glycerite  or  ointment, 
or  some  other  fluid  preparation  may  be  preferred.  The  styptic  collodion 
may  also  be  employed  for  this  purpose,  the  evaporation  of  the  solvent 
leaving  the  surface  covered  with  a  thin  layer  of  collodion  impregnated 
with  tannic  acid.  Tannic  acid  is  used  as  a  mouth  wash  in  cases  of  swol- 
len gums,  or  relaxed  throat,  and  may  here  be  prescribed  in  a  flavored 
solution  or  in  the  form  of  lozenges,  of  which  the  pharmacopeia  offers 
a  choice.  In  certain  forms  of  diarrhoea  the  astringent  action  of  tannic 
acid  is  of  considerable  value,  and  occasionally  when  such  drugs  as 
cod-liver  oil  cause  diarrhoea,  tannic  acid  prevents  this  action  without 
hindering  their  general  effects.  The  pure  drug  is  seldom  used  in  these 
cases,  as  it  is  liable  to  derange  the  stomach  and  to  form  compounds 
with  the  albumins  before  it  reaches  the  bowel,  and  catechu,  krameria 
or  kino  is  accordingly  prescribed,  either  in  the  form  of  pills  or  in  fluid 
preparations.  Possibly  all  of  these  may  be  replaced  in  the  early 
future  by  such  artificial  compounds  as  tannigen  or  tannalbin.  Tannic 
acid  stops  hemorrhage  by  precipitating  the  proteids,  when  it  comes 
into  immediate  contact  with  the  bleeding  point,  but  it  is  not  of  so 
much  value  for  this  purpose  as  some  of  the  metallic  astringents. 
When  the  bleeding  point  can  be  reached  directly,  the  pure  acid  is  used, 
but  for  hemorrhage  of  the  intestine  or  stomach  one  of  the  extracts  is 
preferred.  Large  enemata  containing  tannic  acid  have  been  advised 
in  cholera,  dysentery  and  similar  conditions. 

In  cases  of  poisoning  with  metals  and  alkaloids,  tannic  acid  is  often 
used  to  cause  their  precipitation  in  the  stomach,  but  the  tannate  formed 
must  be  removed  at  once,  as  it  is  gradually  dissolved  in  the  digestive 
fluids.  The  administration  of  tannic  acid  is  therefore  only  a  tem- 
porary expedient  to  allow  of  active  measures  being  taken  to  empty  the 
stomach. 


ANTHELMINTICS.  1 15 

Some  individuals  are  peculiarly  susceptible  to  the  action  of  tannic 
acid,  which  induces  local  irritation  and  inflammation  wherever  it  is 
applied  in  these  cases. 

BlBLIOGKAPHY. 

Hennig.     Arch.  f.  physiol.  Heilkunde,  xii.,  p.  599. 

Rosenstim.     Rossbach's  Pharmakologische  Untersuchungen,  ii.,  p.  78. 

Lewin.     Virchow's  Archiv,  Ixxxi.,  p.  74.  Deutsch.  med.  Woch.,  1904,  p.  803. 

Stockman.  Brit.  Med.  Journ.,  1886,  ii.,  p.  1077.  Arch.  f.  exp.  Path.  u.  Pharm., 
xi.,  p.  147. 

Morner.     Ztschr.  f.  phys.  Chera.,  xvi.,  p.  255. 

Heinz.     Virchow's  Arch.,  cxvi.,  p.  220. 

Schiitz.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii.,  p.  202. 

Meyer.     Deutsch.  med.  Woch.,  1894,  p.  626. 

Gottleib.     Ibid.,  1896,  p.  163. 

Host.  Arch.  f.  exp.  Path.  u.  Pharm.,  xxxviii.,  p.  346.  Centrabl.  f.  Physiol.,  xii., 
p.  258. 

Harnack.     Zeitschr.  f.  physiolog.  Chemie,  xxiv.,  p.  115. 

Ftatow.     Deutsch.  med.  woch.  Therap.  Beilag.,  1899,  p.  37. 

Straub.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlii.,  p.  1. 

Gebhart.     Deutsch.  Arch.  f.  klin.  Med.,  Ixvi.,  p.  585. 

IX.     ANTHELMINTICS. 

Anthelmintics  are  drugs  which  are  used  to  kill  or  remove  intestinal 
worms.  They  possess  no  such  mutual  resemblances  in  their  effects  as 
are  met  with  in  the  purgatives,  and  their  arrangement  in  a  class  is 
therefore  artificial ;  at  the  same  time,  they  have  no  marked  affinities 
with  other  groups,  and  it  is  convenient  to  have  those  bodies  which  are 
used  exclusively  for  this  purpose  placed  together. 

In  order  to  possess  any  value  as  an  anthelmintic,  a  drug  must,  of 
course,  act  more  strongly  on  the  parasite  than  on  the  host,  and  this  more 
intense  effect  may  be  attained  either  by  a  specific  action  on  the  para- 
site, or  by  the  drug  failing  to  be  absorbed  from  the  alimentary  canal. 
As  a  matter  of  fact,  the  anthelmintics,  with  the  possible  exception  of 
pelletierine,  have  no  such  specific  action,  and  their  use  is  rendered  pos- 
sible only  by  their  slow  absorption.  In  this  point  they  resemble  the 
purgatives,  from  which  they  differ,  however,  in  causing  little  or  no 
irritation  in  the  stomach  or  bowel. 

Anthelmintics  are  often  divided  into  vermicides  and  vermifuges, 
according  as  they  kill  or  merely  cause  the  expulsion  of  the  worm,  but 
as  this  is  determined  largely  by  the  quantity  which  comes  in  contact 
with  the  parasite  and  the  rapidity  with  which  the  bowel  is  evacuated, 
the  distinction  is  imaginary. 

Before  the  administration  of  an  anthelmintic,  the  bowel  ought  to  be 
emptied  of  its  contents  as  far  as  possible  by  a  light,  easily  digested 
diet  and  a  laxative,  and  a  brisk  purge  ought  to  follow  some  hours 
later,  in  order  to  remove  the  dead  or  stupefied  worm.  The  anthel- 
mintic is  often  prescribed  along  with  a  purge. 

A  number  of  drugs  belonging  to  other  groups  are  used  occasionally 
as  anthelmintics.  Thus  several  of  the  volatile  oils — tansy,  turpentine — 
have  some  reputation  ;  and  chloroform  is  also  administered  occasionally 
by  the  mouth  for  its  action  on  the  parasites,  but,  like  jt-he  volatile  oils, 


116  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

is  apt  to  produce  gastric  and  intestinal  irritation.  The  less  easily 
absorbed  antiseptics,  such  as  naphthol,  have  been  used  with  good 
results,  and  thymol  is  regarded  as  a  specific  in  cases  of  uncinariasis. 
Large  enemata  of  salt  solution,  or  of  infusion  of  quassia,  are  thrown 
into  the  rectum  when  the  worms  infest  the  large  intestines.  The 
anthelmintics  proper  may  be  divided  into  those  which  are  used  for 
tapeworm,  of  which  male  fern,  cusso  and  pomegranate  are  the  most 
largely  used,  and  those  for  the  round  worm  of  which  santonin  is  the 
chief.  Besides  these,  an  enormous  number  of  substances  have  been 
used  popularly  as  anthelmintics,  but  have  not  been  shown  to  have  any 
advantages  over  those  more  generally  adopted  in  medical  practice. 


Male  Fern  (Aspidium  Filix-mas). 

A  number  of  ferns  contain  bodies  which  present  considerable  re- 
semblance to  each  other  from  a  chemical  as  well  as  from  a  pharma- 
cological point  of  view,  and  which  may  therefore  be  classed  together, 
at  any  rate  until  further  information  is  available  regarding  them.  The 
best  known  of  these  is  the  male  fern  (Aspidium  Filix-mas). 

The  active  constituent  of  this  remedy  was  supposed  to  be  Filicic  Acid  by 
Poulsson,  but  Boehm  has  found  a  series  of  neutral  and  acid  bodies  present  in 
much  larger  amount — Aspidin,  Aspidinin,  Flavaspidic  Acid,  Albaspidin  and 
Aspidinol — of  which  aspidin  is  contained  in  largest  quantity  in  the  root  and  is 
the  most  important,  although  aspidinin  is  also  highly  poisonous.  A  number  of 
these  constituents  have  been  shown  to  be  derivatives  of  phloroglucin,  and  it  is 
probable  that  they  are  all  closely  related.  The  therapeutic  and  toxicological 
effects  of  the  male  fern  are  to  be  attributed  then  to  aspidin,  aspidinin,  and  filicic 
acid.  * 

Action. — The  extract  or  oleoresin  of  male  fern,  which  is  the  only  om 
of  these  plants  used  in  regular  medicine,  as  a  general  rule  passes 
through  the  bowel  without  causing  any  symptoms  whatever.  The 
quantity  of  active  substance  dissolved,  while  sufficient  to  destroy  the 
parasite,  is  too  small  to  produce  any  effects  on  the  host,  and  escapes 
with  the  other  contents  of  the  bowel,  or  if  absorbed  does  not  cause  any 
symptoms.  In  some  cases,  however,  where  large  quantities  are  admin- 
istered, or  where  some  unknown  conditions  favor  the  absorption  and 
retention  of  an  unusually  large  amount  of  the  active  constituents,  grave 
and  even  fatal  symptoms  may  supervene.  These  consist  in  vomiting 
and  purging,  with  acute  pain  in  the  abdomen,  muscular  weakness 
confusion  and  somnolence,  with  occasional  twitching  of  the  muscles,  01 
slight  convulsive  movements,  collapse,  coma  and  death.  The  stomach 

1  Nearly  related  bodies  have  been  found  in  Aspidium  athamanticum  (Uncomocomo), 
which  contains  two  forms  of  Pannic  Acid,  and  in  Aspidium  spinulosum,  while  smallei 
quantities  of  acids  occur  in  a  large  number  of  ferns. 

Several  of  these  ferns  enjoy  a  reputation  as  anthelminics  for  tapeworm,  and  their 
virtues  are  generally  considered  due  to  these  bodies,  although  Kobert  maintains  that 
it  is  partly  to  be  ascribed  to  the  fixed  or  volatile  oils  which  accompany  them. 


ANTHELMINTICS.  117 

and  intestine  are  found  congested  and  swollen,  and  sometimes  covered 
with  small  ecchymoses.  In  some  cases  icterus  has  been  observed  to 
follow  the  administration  of  male  fern,  probably  from  the  duodenal 
catarrh,  but  possibly  from  destruction  of  the  red  blood  cells,  the  num- 
ber of  which  has  been  found  to  be  diminished  in  some  instances 
(Georgiewsky).  In  other  cases  permanent  or  temporary  blindness 
has  resulted  from  neuritis  and  subsequent  atrophy  of  the  optic  nerve. 

In  the  rabbit,  filicic  acid  produces  very  similar  symptoms.  The  congestion 
of  the  stomach  and  intestine  is  evidently  due  to  the  local  irritation  produced 
by  the  poison,  while  the  other  symptoms  point  to  changes  induced  in  the 
central  nervous  system.  It  would  seem  probable  that  the  spinal  cord  is 
affected  in  the  same  way  as  by  strychnine,  for  the  reflex  excitability  is  dis- 
tinctly increased.  The  higher  parts  of  the  central  nervous  system  seem  to 
be  depressed,  and  the  paralysis  of  the  respiratory  centre  is  the  cause  of 
death,  although  the  heart  is  also  weakened  by  filicic  acid.  Inflammation  of 
the  kidney  is  said  by  some  authors  to  occur,  and  in  some  cases  Poulsson 
found  evidence  of  glycuronic  acid  in  the  urine. 

In  the  frog,  a  mixture  of  depression  and  stimulation  of  the  central 
nervous  system  is  produced  by  filicic  acid,  along  with  a  distinct  diminution 
in  the  strength  of  the  skeletal  muscles  and  the  heart. 

Aspidin  injected  into  the  frog  causes  dyspnoea  followed  by  paralysis  of  the 
spontaneous  and  respiratory  movements  ;  fibrillary  twitching  of  the  muscles 
sets  in  after  some  time  and  is  succeeded  by  convulsive  movements  or  tonic 
spasms,  which  indicate  an  increased  activity  of  the  reflexes  of  the  spinal 
cord.  The  heart  is  depressed  and  eventually  paralyzed,  and  the  peripheral 
muscles  are  also  weakened.  The  muscular  tissue  of  the  invertebrates  is 
more  powerfully  affected  by  the  constituents  of  male  fern  and  Straub  attributes 
its  action  on  the  tapeworm  to  its  paralyzing  muscle.  Mammals  do  not  seem 
to  be  affected  by  aspidin  injected  hypodermically  or  administered  by  the 
mouth,  but  when  it  is  introduced  directly  into  the  blood  vessels,  it  proves 
fatal  by  paralyzing  the  respiratory  centre.  Aspidinin  induces  very  similar 
symptoms  in  the  frog,  while  the  other  constituents  are  less  active. 

The  blindness  which  has  been  observed  in  some  cases  of  male  fern  poison- 
ing has  also  been  produced  in  dogs  ;  it  occurs  chiefly  in  young,  weakly  and 
anaemic  individuals. 

Pannic  acid  differs  from  filicic  chiefly  in  its  acting  more  strongly  on  muscle 
and  less  on  the  central  nervous  system  of  the  frog. 

PREPAKATIONS. 

Aspidium  (U.«S.  P.),  Male  fern,  the  rhizome  of  Dryopteris  Filix-mas  and  of 
Dryopteris  marginalis,  Filix  Mas  (B.  P.),  Male  fern,  the  rhizome  of  Aspidium 
Filix-mas. 

OLEORESINA  ASPTDII  (U.  S.  P.),  2-8  c.c.  (£-2  fl.  drs.). 

EXTRACTUM  FILICTS  LIQUIDUM  (B.  P.),  45-90  mins. 

The  oleoresin  (U.  S.  P.)  and  the  liquid  extract  (B.  P.)  are  practically  iden- 
tical in  composition. 

Therapeutic  Uses.— Male  fern  is  used  exclusively  in  the  treatment  of 
tapeworm  and  of  Anchylostomum  duodenale.  Previous  to  its  admin- 
istration the  bowel  ought  to  be  emptied,  as  far  as  possible,  by  a  moder- 
ately light  diet  for  one  or  two  days  and,  where  necessary,  by  a  purgative. 
The  oleoresin,  or  liquid  extract,  is  then  to  be  administered  in  the  form  of 
pills  or  enclosed  in  a  capsule  or  suspended  in  mucilage,  and  another 
purgative  is  required  some  6-12  hours  later.  In  case  the  parasite  fails 
to  be  dislodged,  several  days  ought  to  be  allowed  to  elapse  before  a 


118  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

second  dose  is  given.  Poulsson  recommends  that  oily  substances  be 
avoided  during  the  "cure,"  as  they  dissolve  the  filicic  acid,  and  thus 
promote  its  absorption.  It  is  impossible  to  estimate  the  importance  of 
this  fact  since  Boehm  has  discovered  the  other  active  constituents,  but 
it  is  certainly  suggestive  that  in  many  cases  of  poisoning  with  male  fern 
castor  oil  had  been  given  along  with  it  or  soon  after.  Marked  anaemia, 
general  debility,  and  chronic  alcoholism  seem  to  predispose  to  male-fern 
poisoning,  and  the  drug  is  accordingly  to  be  used  with  care  in  these 
conditions. 

BIBLIOGRAPHY. 

Poulsson.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix.,  p.  1  ;  xxxv.,  p.  97;  xli.,  p.  246. 

Robert.     Therap.  Monatsheft,  1893,  p.  136. 

Birch-Hirschfeld.     Graefe's  Arch.  f.  Ophthalmologie,  1.,  p.  225. 

Masius.     Bull  de  1'Ac.  de  Med.  de  Belg.,  29  June,  1895. 

Georgiewsky.     Ziegler's  Beitriige,  xxiv.,  p.  1.' 

Boehm.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv.,  p.  1 ;  xxxviii.,  p.  35. 

Straub.     Ibid.,  xlviii.,  p.  1. 

Walko.     Deutsch.  Arch.  f.  klin.  Med.,  Ixiii.,  p.  348. 

Cusso. 

Cusso,  or  Kousso,  contains  a  neutral  body,  Kosotoxin,  which  is  sol- 
uble in  alcohol  and  in  alkaline  fluids,  but  is  insoluble  in  water ;  it  is 
probably  nearly  related  to  the  active  constituents  of  male  fern,  which 
it  resembles  somewhat  in  its  pharmacological  action. 

Cusso  has  a  bitter,  somewhat  astringent  taste,  and  sometimes  causes 
nausea  and  vomiting  and  some  looseness  of  the  bowels.  In  rare  cases 
prostration  and  collapse,  with  irregularity  of  the  pulse,  are  said  to 
have  occurred  from  its  use. 

In  the  frog,  kosotoxin  paralyzes  the  nerve  ends  like  curara,  and  has 
a  specific  action  on  the  striped  muscular  tissue,  which  it  weakens  and 
eventually  paralyzes.  The  heart  muscle  undergoes  similar  changes.  In 
mammals  the  muscular  action  is  well  developed,  but  is  accompanied  by  some 
stimulation  of  the  medullary  centres,  indicated  by  rapid,  dyspnoeic  breath- 
ing, salivation  and  vomiting.  The  stools  are  often  fluid,  and  the  urine  is 
increased  in  amount.  When  it  is  injected  directly  into  the  circulation,  some 
convulsive  movements  are  often  observed,  and  the  heart  is  weakened  and 
paralyzed.  Kosotoxin  seems  to  be  a  general  protoplasm  poison,  as  is  indi- 
cated by  its  action  on  muscle,  and  by  its  retarding  the  growth  of  yeast. 

PREPARATIONS. 

Cusso  (U.  S.  P.,  B.  P.)  (Kousso  or  Brayera),  the  female  inflorescence  of 
Hagenia  Abyssinica  (Brayera  anthelmintica). 

Cusso  is  generally  given"  by  suspending  15  G.  (£  oz.)  of  the  powdered  flowers 
in  water.  Kosotoxin  has  not  yet  been  prescribed  for  therapeutic  purposes.  The 
usual  preliminary  treatment  ought  to  be  instituted,  but  no  purge  is  required 
after  Cusso  as  a  general  rule. 

Therapeutic  Uses.  —  Cusso  is  used  exclusively  as  an  anthelmintic  in 
cases  of  tapeworm. 

BIBLIOGRAPHY. 

Leichsenring.     Arch.  d.  Pharm.,  ccxxxii.,  p.  50. 
Handmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvi.,  p.  138. 


ANTHELMINTICS.  119 

Granatum. 

The  bark  of  the  pomegranate  contains  a  very  large  amount  of  tannic 
acid  (20-25  per  cent.),  along  with  numerous  alkaloids,  of  which 
Pdletierine,  or  Punirine,  and  Isopunicine  alone  are  active  in  ordinary 
doses.  All  the  pomegranate  alkaloids  are  closely  related  chemically 
to  each  other  and  to  tropine  (see  atropine).  None  of  them  can  be 
classed  among  the  more  active  poisons  as  far  as  man  and  the  higher 
animals  are  concerned. 

In  man,  large  doses  cause  heaviness,  confusion,  giddiness  and  very 
marked  weakness  of  the  limbs.  The  consciousness  is  but  little  affected, 
but  the  sight  is  often  dim  and  uncertain,  and  in  one  case  complete 
blindness  persisted  for  several  days.  Occasionally  nausea  and  discom- 
fort in  the  abdomen  are  complained  of,  and  more  rarely  vomiting, 
tremors  and  cramps  of  the  leg  muscles  are  produced  ;  the  gastric  symp- 
toms are  perhaps  due  to  the  large  quantity  of  tannic  acid  in  the  drug 
rather  than  to  the  alkaloids. 

In  the  frog  and  in  most  mammals,  pelletierine  causes  a  distinct  increase  in 
the  reflex  irritability  of  the  spinal  cord  and  medulla  oblongata,  along  with 
some  depression  of  the  higher  divisions  of  the  central  nervous  system.  Very 
large  doses  weaken  or  paralyze  the  conductivity  of  the  nerve  plates  in  the  frog, 
like  curara.  The  heart  muscle  is  also  acted  on  and  its  pulsations  are  slowed  in 
the  frog,  although  they  may  be  temporarily  augmented  in  force. 

Pelletierine  and  isopunicine  have  a  specific  action  on  tapeworms, 
for  Schroeder  found  that  a  solution  of  one  part  in  10,000  was  suffi- 
cient to  kill  them  in  ten  minutes,  while  a  stronger  solution  had  prac- 
tically no  effect  upon  other  intestinal  worms. 

PREPARATIONS. 

Granatum  (U.  S.  P.),  Granati  Cortex  (B.  P.),  Pomegranate  bark,  the  bark 
of  the  stem  and  root  of  Punica  Granatum. 

Decoctum  Granati  Corticis  (B.  P.),  |-2  fl.  oz. 

Fluidextractum  Granati  (U.  S.  P.),  2  c.c.  (30  mins.). 

PelletierincB  Tatinas  (U.  S.  P.),  a  mixture  in  varying  proportions  of  the  tan- 
nates  of  four  alkaloids  (punicine,  isopunicine,  inethylpunicine  and  pseudo- 
punicine),  obtained  from  the  pomegranate.  Dose,  0.25  G.  (4  grs.). 

Granatum  is  used  as  a  decoction  formed  of  30-60  G.  (1-2  oz.)  in  250  c.c.  of 
water  (£  pt.),  to  be  taken  in  two  parts,  at  an  interval  of  one  hour.  The  bark 
ought  to  be  as  fresh  as  possible,  as  the  alkaloids  decompose  on  keeping.  The 
presence  of  large  quantities  of  tannic  acid  renders  the  decoction  very  unpleasant 
to  the  taste,  and  flavoring  substances  are  therefore  generally  prescribed  with  it, 
or  pelletierine  tannate  may  be  ordered. 

Therapeutic  Uses. — Granatum  is  used  exclusively  as  an  anthelmintic. 
The  preliminary  treatment  is  the  same  as  that  given  under  aspidium, 
and  a  purge  ought  to  be  given  J-2  hours  after  the  decoction. 

BIBLIOGRAPHY. 

Dujardin-Beaumetz.     Bull,  de  Therap.,  xcviii.,  p.  433. 

Eerenger-Feraud.     Ibid.,  xcvii.,  pp.  8,  337,  391. 

v.  Schroeder.     Arch.  f.  exp.  Path.  u.  Pharm.,  xviii.,  p.  381,  and  xix.,  p.  290. 

Henze.     Pfliigei-'s  Arch.,  xcii.,  p.  464. 


120  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

Kamala  is  a  reddish-brown  powder  which  consists  of  the  minute  glands  and 
hairs  obtained  from  the  surface  of  the  fruits  of  Mallotus  Philippensis.  It  con- 
tains two  or  more  substances  which  have  been  termed  Kamalin,  Rottlerin  or  Mal- 
lotoxin,  and  which  are  probably  neutral  bodies  like  kosotoxin,  but  it  is  not 
known  which  of  these  is  the  active  constituent.  Kamala  is  used  in  cases  of 
tapeworm  in  doses  of  2-8  G.  (30  grs.-|  oz.)  suspended  in  water.  It  acts  as  an 
intestinal  irritant,  causing  purging  and,  more  rarely,  nausea  and  vomiting.  No 
purge  is  necessary,  therefore,  after  the  powder.  An  alcoholic  tincture  of 
kamala  has  been  found  quite  as  efficient  as  the  powder. 

Pepo  (pumpkin  seed)  contains  a  fixed  oil  and  resin,  and  the  latter  seems 
to  have  considerable  power  as  an  anthelmintic,  although  this  is  disputed 
by  some  authorities.  No  symptoms  are  produced  by  very  large  quantities  of 
the  powdered  seeds. 

Pepo  (IT.  S.  P.),  the  seed  of  Cucurbita  pepo,  Pumpkin  seed,  is  generally 
administered  in  doses  of  60-120  G.  (2-4  oz.),  the  powdered  seed  being  sus- 
pended in  an  emulsion  or  in  sugar  or  honey.  Pumpkin  seed  has  no  laxa- 
tive effect  and  its  administration  is,  therefore,  to  be  followed  by  a  purge. 
The  resin  has  been  used  with  good  effects  in  some  cases. 

Santonin. 

Santonin  (C15H18O3)  is  an  anhydride  or  lactone  of  santoninic  acid, 
which  is  formed  from  it  by  the  action  of  alkalies,  and  is  a  derivative  of 
naphtalene.  It  occurs  in  Artemisia  pauciflora  along  with  a  nearly  related 
body  (artemisin)  and  a  volatile  oil  (cineol).  Santonin  is  very  insoluble 
in  water,  but  is  dissolved  by  alkalies,  with  which  it  forms  sautoninates. 

Action. — Owing  to  its  insolubility  in  water,  santonin  has  only  a 
slightly  bitter  taste  in  the  mouth.  It  is  partially  dissolved  in  the 
stomach  and  absorbed,  but  enough  passes  into  the  bowel  to  effect  the 
removal  of  some  forms  of  intestinal  worms.  Under  special  conditions 
it  is  possible  that  the  greater  part  of  the  santonin  may  be  absorbed  in 
the  stomach,  however,  and  general  poisoning  results  without  the  para- 
sites being  affected.  A  certain  amount  of  absorption  occurs  in  every 
case,  as  is  shown  by  the  disorders  of  color  vision  and  by  the  yellow 
coloration  of  the  urine.  At  first  objects  appear  of  a  bluish  color  to 
the  patient,  but  this  aberration  is  of  comparatively  short  duration  and 
may  in  fact  pass  unnoticed.  It  is  followed  by  a  much  longer  period  of 
"  yellow  sight "  or  xanthopsia,  during  which  objects  that  are  brightly 
illuminated  seem  to  have  a  yellow  tinge,  blue  seems  green,  and  violet 
is  indistinct,  although  in  dimmer  lights  the  violet  may  still  predomi- 
nate. In  severe  poisoning  the  appreciation  of  the  darker  colors  becomes 
very  imperfect,  and  violet  and  even  blue  may  fail  to  be  distinguished 
from  black.  In  general  the  violet  end  of  the  spectrum  is  shortened, 
while  the  yellow  impresses  the  retina  more  vividly  than  normally. 
Sometimes  "  hallucinations  "  of  vision  are  said  to  occur  under  santonin, 
although  these  seem  to  be  unimportant ;  thus  one  observer  saw  green 
globes  on  a  violet  background  whenever  he  closed  his  eyes.  These 
aberrations  of  sight  are  the  most  generally  observed  symptoms  produced 
by  santonin,  but  in  some  cases  the  sense  of  taste  and  smell,  and  more 
rarely  the  hearing,  are  also  deranged.  These  symptoms  all  pass  off  in 
the  course  of  a  few  hours,  a  second  stage  of  "  violet  sight "  occasionally 
intervening  before  complete  recovery. 


ANTHELMINTICS.  121 

The  symptoms  produced  by  the  absorption  of  large  quantities  of 
santonin  are  so  uniform  in  man  and  the  other  mammals  that  it  is  suffi- 
cient to  enumerate  those  observed  in  experiments  on  the  dog.  The 
first  distinct  effects  are  generally  twitching  of  the  muscles  of  the 
head,  frequently  beginning  on  one  side.  These  are  followed  by  roll- 
ing of  the  eyes,  grinding  of  the  teeth,  flexion  and  extension  of  the 
neck  and  rotation  of  the  head  from  side  to  side,  later  by  regular  epi- 
leptiform  convulsions  in  which  the  animal  is  first  thrown  into  opistho- 
tonos  and  then  into  clonic  spasms  of  the  limbs  and  trunk.  These 
are  interrupted  by  intervals  of  repose  during  which  a  curious  momen- 
tary contraction  of  all  the  muscles  of  the  body  is  often  noticed.  Dur- 
ing the  convulsive  seizures  the  respiration  is  irregular  and  insufficient, 
and  in  fatal  cases  it  fails  to  return  after  the  convulsion  passes  off,  and 
the  animal  dies  of  asphyxia.  In  man,  some  confusion,  nausea  and 
vomiting  occasionally  occur  after  quantities  which  are  too  small  to 
produce  convulsions,  and  in  several  cases  aphasia  has  been  observed. 
In  frogs,  convulsions  are  produced  by  santonin  as  in  mammals,  but 
they  are  preceded  by  a  prolonged  stage  of  depression,  \vhich  is  entirely 
absent  in  the  higher  animals. 

These  symptoms  manifestly  point  to  changes  in  the  central  nervous 
system.  The  xanthopsia  is  generally  referred  to  a  specific  action  on 
the  retina,  though  some  hold  that  the  central  apparatus  of  vision  in 
the  brain  is  the  seat  of  the  action.1  The  condition  has  been  ascribed 
to  a  preliminary  stimulation  and  subsequent  depression  of  the  sense 
organs  for  the  perception  of  the  violet  and  eventually  of  the  blue  rays 
of  the  spectrum,  or  more  precisely  to  some  obstruction  to  the  regener- 
ation of  the  substance  in  the  retina  which  normally  appreciates  violet 
rays  (Filehne).  The  clonic  nature  of  the  convulsions  at  once  points 
to  an  affection  of  the  brain  rather  than  of  the  cord,  but  some  dis- 
cussion has  arisen  as  to  how  far  the  cortical  areas  are  involved  and 
how  far  the  symptoms  may  be  explained  by  stimulation  of  the  basal 
ganglia.  The  latest  investigators  have  come  to  the  conclusion  that  the 
epileptiform  convulsions  are  due  for  the  main  part  to  the  stimulation 
of  the  cortex,  while  the  sudden  contractions  observed  in  the  intervals 
of  repose  are  ascribed  to  increased  activity  of  the  parts  lying  between 
the  cerebral  peduncles  and  the  medulla  oblongata.  The  gray  matter 
of  this  division  of  the  central  nervous  system  also  seems  involved  in 
the  clonic  movements,  although  these  are  only  elicited  in  their  full 
strength  through  action  on  the  cerebral  cortex  (Kramer). 

Although  these  parts  of  the  central  nervous  system  are  the  most 
susceptible  to  the  action  of  santonin,  large  quantities  also  affect  the 
cord  after  division  of  the  medulla  oblongata  and  produce  tonic  con- 
vulsions resembling  those  seen  in  strychnine  poisoning. 

The  medullary  centres  seem  to  be  comparatively  little  affected  by 
santonin,  the  respiration  being  interfered  with  during  the  spasms,  but 
returning  to  its  ordinary  rate  and  strength  during  the  intervals.  The 

1  The  view  formerly  held  that  the  yellow  vision  was  due  to  a  yellow  pigmentation  of 
the  vitreous  humor  or  the  retina  is  undoubtedly  erroneous. 


122  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

circulation  is  altered  only  by  the  asphyxia,  and  the  heart  continues  to 
beat  long  after  the  respiration  has  ceased. 

Santonin  undergoes  some  oxidation  in  the  tissues  and  is  excreted  in 
the  faeces  and  urine  in  several  forms,  two  of  which  have  been  exam- 
ined by  Jaffe  and  found  to  be  oxysantonins.  The  urine  and  some- 
times the  faeces  have  a  deep  yellow  color,  which  changes  to  red  or 
purple  when  alkalies  are  added.  A  similar  reaction  is  obtained  from 
the  urine  after  the  administration  of  chrysophanic  acid,  as  in  rhubarb 
or  senna,  and  a  number  of  reactions  are  given  to  distinguish  between 
these  two  pigments,  which,  however,  it  can  scarcely  be  necessary  to  do 
frequently. 

Thus  the  red  of  chrysophanic  acid  is  permanent,  while  that  of  the  san- 
tonin pigment  fades  after  a  time,  and  reducing  agents,  such  as  zinc,  remove 
the  former,  and  not  the  latter,  while  barium  and  calcium  precipitate  the 
chrysophanic  and  not  the  santonin  pigment. 

Santonin  was  formerly  credited  with  some  cholagogueand  diuretic  action, 
but  more  accurate  investigations  have  shown  that  it  has  no  such  effects. 

According  to  Harnack  and  Hochheim,  santonin  lowers  the  temperature  in 
most  animals  by  increasing  the  loss  of  heat  through  dilation  of  the  cuta- 
neous vessels  ;  it  resembles  in  this  respect  several  other  convulsive  poisons 
investigated  by  these  authors. 

Santonin  is  universally  used  as  a  remedy  for  the  round  worm,  As- 
caris  lumbricoides,  and  most  clinicians  believe  that  it  has  a  specific  poi- 
sonous action  on  these  animals,  and  that  its  undoubted  effects  are  due 
to  its  killing  them.  In  experiments  on  the  entozoa  outside  the  body, 
however,  von  Schroeder  found  that  santonin  solutions  were  by  no 
means  fatal  to  them,  and  he  explains  their  therapeutic  effects  by  sup- 
posing that  santonin  renders  the  intestine  so  unpleasant  an  abode 
for  the  parasites  that  they  migrate  from  it  voluntarily  into  the  large 
bowel,  and  are  carried  out  by  the  purgative.  The  worms  are  often 
found  in  active  movement  when  passed  after  santonin,  although  this 
movement  ceases  very  soon  afterward  from  the  exposure  to  cold. 

The  alkaline  salts  of  santoninic  acid  act  in  precisely  the  same  way  as  santonin 
itself,  but  are  less  suitable  as  anthelmintics,  owing  to  their  greater  solubility  and 
rapid  absorption.  A  number  of  santonin  derivatives  have  been  examined  by 
Coppola,  who  found  that  many  of  them  produced  effects  which  were  practically 
identical  with  those  of  santonin,  while  in  others  the  stage  of  convulsions  was 
preceded  by  one  of  depression. 

PREPARATIONS. 

Santonica  (U.  S.  P.),  Levant  wormseed,  the  unexpanded  flower-heads  of 
Artemisia  pauciflora. 

SANTONINUM  (U.  S.  P.,  B.  P.),  C15H18O3,  a  neutral  principle  derived  from 
Santonica.  Santonin  is  colorless  when  freshly  prepared,  but  assumes  a  yel- 
low color  when  exposed  to  the  light.  This  does  not  seem  to  impair  its 
activity  materially,  but  it  is  preferable  to  avoid  it  by  keeping  santonin  in 
amber-colored  vials.  Dose,  0.03-0.1  G.  (£-2  grs.). 

TROCHISCI  SANTONINI,  each  containing  0.03G.  (|  gr.)  of  santonin,  U.  S.P.; 
each  containing  1  gr.,  B.  P. 


ANTHELMINTICS.  123 

Therapeutic  Uses. — Santonin  is  used  almost  exclusively  to  remove 
Ascaris  lumbricoides  from  the  intestine.  It  is  much  less  effective  against 
tapeworm  or  other  intestinal  parasites.  The  lozenges  are  generally 
prescribed,  one  for  children,  two  for  adults,  U.  S.  P.,  while  the  dose  of 
the  B.  P.  lozenge  is  one  for  an  adult.  Lewin  recommends  the  admin- 
istration of  santonin  in  oily  solutions,  especially  in  castor  oil,  as  less  is 
absorbed  from  the  stomach  than  when  it  is  prescribed  in  other  ways. 
The  bowel  ought  to  be  emptied  by  suitable  diet  and  a  laxative  before 
the  santonin  is  administered,  and  a  sharp  purge  ought  to  be  given  2—4 
hours  afterwards  in  order  to  bring  away  the  entozoa. 

Santonin  has  been  advised  in  some  retinal  diseases,  but  the  results 
have  generally  been  unsatisfactory. 

Poisoning.  —  In  cases  of  poisoning,  the  stomach  and  bowel  ought  to 
be  evacuated  as  rapidly  as  possible  by  the  use  of  emetics  or  of  the  stom- 
ach tube,  and  of  purgatives  cr  enema.  The  convulsions  may  be  con- 
trolled by  the  use  of  chloroform  or  ether.  The  xanthopsia  requires  no 
treatment,  and  is  not  to  be  regarded  as  heralding  any  dangerous  develop- 
ments, as  it  occurs  to  some  degree  in  the  great  majority  of  cases  in 
which  santonin  is  administered. 

BIBLIOGRAPHY. 

Binz.     Arch.  f.  exp.  Path.  u.  Pharm.,  vi.,  p.  300. 

Lewin.     Berl.  klin.  Woch.,  1883,  p.  170. 

Luchsinger.     Pfl tiger's  Arch.,  xxxiv.,  p.  293. 

Jaffe.     Ztschr.  f.  klin.  Med.,  xvii.   Suppl.,  p.  7.     Ztsch.  f.  phys.  Chem.,  xxii.,  p.  538. 

Falck.     Deutsche  Klinik,  1860,  p.  257. 

Kramer.     Ztschr.  f.  Heilkunde,  xiv.,  p.  303. 

Turtschaninoiv.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv.,  p.  208. 

v.  Schroeder.     Ibid.,  xix.,  p.  290. 

Nayel.     Ztschr.  f.  Psychol.  u.  Phys.  d.  Sinnesorgane,  xxvii.,  p.  267. 

Harnack.  Zts.  f.  klin.  Med.,  x'xv.,  p.  16;  Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi., 
pp.  272,  447. 

Rose.  Virchow's  Arch.,  xvi.,  p.  233;  xviii.,  p.  15;  xix.,  p.  522;  xx.,  p.  245; 
xxviii.,  p.  30. 

Hufner.     Arch.  f.  Ophthalmol.,  xiii.,  p.  309. 

Preyer.     Pfluger's  Arch.,  i.,  p.  299. 

Coppola.     Maly's  Jahresbericht,  xvii.,  p.  92. 

Filehne.     Pfl  tiger's  Arch.,  Ixxx.,  p.  96. 

SPIGELIA. 

Another  remedy  used  in  cases  of  round  worm  is  pink  root,  Spigelia  mari- 
tima  (U.  S.  P.),  the  active  principle  of  which  is  unknown,  although  an 
alkaloid,  spigeline,  is  said  to  occur  in  it.  Occasional  cases  of  poisoning  have 
been  observed,  especially  in  children,  the  symptoms  consisting  in  flushing 
and  dryness  of  the  skin,  often  with  some  cedematous  swelling  of  the  face, 
delirium  and  sopor  followed  by  dimness  of  sight  or  temporary  blindness. 
In  frogs  spigelia  appears  to  depress  the  brain  and  spinal  cord,  and  the  heart 
beats  more  slowly  and  weakly,  while  in  rabbits  the  most  prominent  symp- 
toms arise  from  the  breathing,  which  becomes  slow  and  labored  and  finally 
ceases  in  a  convulsive  attack.  In  the  dog  and  cat  its  injection  is  followed 
by  vomiting,  great  weakness  and  incoordination  of  the  movements,  restless- 
ness, rapid  dyspnoeic  respiration  and  finally  by  stupor,  coma  and  death  from 
failure  of  the  respiratory  centre. 

Spigelia  (U.  S.  P.),  the  rhizome  and  roots  of  Spigelia  uiarilandica. 


124  ORGANIC  SUBSTANCES  ACTING  LOCALLY. 

Fluidextractum  Spigelice  (U.  S.  P.),  4-8  c.c.  (1-2  fl.  drs.). 

The  fluidextract  is  used  to  remove  round  worms,  which  it  seems  to  effect  in 
very  much  the  same  way  as  santonin.  It  ought  to  be  preceded  and  followed  by 
a  purge. 

One  of  the  volatile  oil  series  which  is  frequently  used  as  an  anthelmintic  is 
that  obtained  from  Chenopodium  ambrosioides  or  American  worm-seed. 

Oleum  Chenopodii  (U.  S.  P.),  0.2-0.3  c.c.  (3-5  mins.).  The  oil  is  admin- 
istered on  sugar  or  in  an  emulsion. 


PART  II. 

ORGANIC    SUBSTANCES    CHARACTERIZED 

CHIEFLY  BY  THEIR  ACTION   AFTER 

ABSORPTION. 

I.    NARCOTICS   OF  THE  METHANE   SERIES. 
ALCOHOL-CHLOROFORM  GROUP. 

A  LARGE  number  of  the  derivatives  of  the  methane  series  are 
characterized  by  the  production  of  depression  of  the  central  nervous 
system,  more  especially  of  the  cerebrum,  and  some  of  them  are  per- 
haps the  most  extensively  employed  of  all  drugs.  With  the  exception 
of  alcohol,  which  has  been  known  since  prehistoric  times,  the  use  of 
the  members  of  this  series  scarcely  extends  over  more  than  half  a 
century. 

From  the  large  number  of  substances  belonging  to  this  division  of 
organic  chemistry  which  are  possessed  of  narcotic  powers,  it  would  seem 
that  the  combination  of  carbon  and  hydrogen  in  the  form  characteristic 
of  this  series  is  possessed  of  a  special  relation  to  the  protoplasm  of 
the  nerve  cells,  or  in  other  words,  carbon  radicles  combined  in  open 
chain  form  are  possessed  of  specific  depressant  powers.  As  a  general 
rule  the  greater  the  number  of  these  radicles  contained  in  the  chain, 
the  more  powerful  the  action,  provided  the  substance  is  not  changed 
so  as  to  become  incapable  of  absorption.  Thus,  in  the  alcohol  series 
a  regularly  ascending  scale  of  toxicity  is  met,  commencing  with  methyl 
and  ethyl  and  passing  through  propyl,  butyl  and  amyl  alcohols,  of 
which  each  succeeding  member  is  more  poisonous  than  its  predecessor. 
The  later  members  of  the  series,  however,  become  less  soluble  in  the 
body  fluids,  are  less  easily  absorbed,  and  therefore  less  toxic. 

The  toxicity  of  these  bodies  may  also  be  reduced  or  removed  completely  by 
the  presence  of  acid-forming  groups.  Thus  ethyl  alcohol  (CH3 — CH2OH) 
is  a  powerful  depressant,  but  propionic  acid  (CH3 — CH2 — COOH)  is  entirely 
inactive  in  this  direction.  Again,  one  hydroxyl  group  in  a  substance  does 
not  remove  its  narcotic  action,  while  two  hydroxyls  reduce  it  very  consider- 
ably or  may  destroy  it  entirely  ;  thus  ethyl  alcohol  (CH3 — CH2OH)  is  prob- 
ably quite  as  active  as  ethane  (CH3— CH3),  but  glycol  (CH2OH— CH2OH)  is 
almost  inactive.  A  still  more  striking  example  of  the  effects  of  several 
hydroxyl  groups  is  seen  in  the  comparison  of  propyl  alcohol  (CH3 — CH2 
— CH2OH)  with  glycerin  (CH2OH— CHOH— CH2OH),  the  former  being  a 
powerful  depressant,  while  the  latter  is  practically  devoid  of  any  such  action 
on  the  central  nervous  system.  Compounds  of  the  fatty  series  may  also  lose 
their  characteristic  effects  by  their  combination  with  more  active  radicles. 
Thus  ethane  (C2H6)  is  a  member  of  the  narcotic  series,  but  ethyl  nitrite 

125 


126  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

(C2H5O — NO)  cannot  be  classed  with  it,  because  the  — O— NO  group  has  a 
very  powerful  and  entirely  different  effect ;  very  small  quantities  of  ethyl 
nitrite  are  required  to  produce  the  nitrite  effect,  so  that  the  depressant  action 
is  pushed  into  the  background.  Members  of  the  methane  series  often  lose 
their  depressant  action  when  combined  with  nitrogen  so  as  to  form  substi- 
tuted ammonia.  Thus  trimethylamine  (N(CH3)3)  has  no  depressant  action, 
although  each  of  the  methyl  radicles  alone  would  possess  it.  Again,  the  sub- 
stitution of  a  member  of  the  aromatic  series  for  one  of  the  fatty  substances 
sometimes  changes  the  action  from  that  characteristic  of  the  alcohol-chloro- 
form group  to  that  of  the  benzol  series.  For  example,  ether  (C2H5 — O — C2H.) 
is  one  of  the  most  valuable  anaesthetics,  but  if  one  ethyl  radicle  be  substi- 
tuted by  phenyl  (C6H5— O — G2H5),  it  loses  this  property  entirely.  Others, 
however,  retain  their  depressant  action,  as,  for  example,  acetophenone 
(C6H5-CO-CH3). 

A  very  interesting  hypothesis  has  recently  been  suggested  by  Meyer l 
and  Overton 2  to  explain  why  so  many  of  the  bodies  of  this  series  act 
as  narcotics.  Practically  all  of  them  are  more  soluble  in  lecithin  and 
cholesterin  than  MI  water  and  accordingly  when  they  reach  the  blood 
they  tend  to  accumulate  in  the  nerve  cells,  which  are  rich  in  cholesterin 
and  lecithin.  Here  they  may  be  supposed  to  partially  dissolve  these 
constituents,  or,  at  any  rate,  to  change  their  relations  to  the  rest  of  the 
nerve  cells  and  this  derangement  of  their  normal  condition  leads  to 
impairment  of  the  function  of  these  cells,  or  narcosis.  But  m-any  other 
substances  (e.  g.,  many  of  the  benzol  derivatives)  possess  these  physical 
properties  equally  with  the  members  of  the  methane  series,  and  yet 
induce  no  narcosis  proper,  so  that  though  the  physical  characters  of 
these  drugs  may  probably  be  important  factors  in  their  action,  they 
cannot  be  held  to  determine  it  solely. 

It  is  impossible  to  enumerate  here  all  the  substances  of  this  series 
which  possess  more  or  less  depressant  action  on  the  nerve  centres.  A 
very  large  number  of  them  have  been  the  subject  of  investigation,  but 
only  a  few  of  them  have  become  established  remedies. 

Among  the  hydrocarbons  the  fifth,  Pentane,  and  the  eighth,  Octane,  have 
been  proposed  as  anaesthetics  for  short  operations,  but  have  never  received 
an  extensive  trial.  Some  of  the  unsaturated  hydrocarbons  have  also  been 
suggested,  such  as  Amylene,  which  was  introduced  by  Snow,  but  was  found1 
to  vary  exceedingly  in  its  properties,  and  proved  to  be  a  mixture  of  several 
isomers.  One  of  these  has  lately  been  isolated  and  recommended  for  short 
operations  under  the  name  of  Pental  ( (CH3)2=  C  —  CH  —  CH3).  Another 
unsaturated  hydrocarbon  which  has  been  shown  to  possess  narcotic  proper- 
ties is  Acetylene,  but  its  action  on  the  heart  is  said  to  preclude  its  use  in 
practical  therapeutics. 

Among  the  alcohols,  Ethyl  alcohol  (C2H.HO)  stands  preeminent  from  its 
extensive  use  in  therapeutics  as  well  as  from  its  importance  in  dietetics  and 
as  a  poison.  Other  alcohols  have  been  found  to  resemble  it  in  action,  but  the 
only  one  that  has  been  introduced  into  therapeutics  is  Amylene  hydrate,  or 
tertiary  isoamyl  alcohol  (  (CH3)2C(OH)CH2CH3),  which  has  been  recommended  as 
a  hypnotic. 

The  ethers  contain  one  very  important  member  in  Ethyl  ether  ( (C2H5)2O), 
which  is  perhaps  the  best  anaesthetic  in  use. 

1  Arch.  f.  exp.  Path.  u.  Pharm.,  xlii.,  p.  109,  and  xlvi.,  p.  338. 

2  Studien  u.  d.  Narkose.     Jena,  1901.     Gottlieb.     Ergeb.  d.  Physiol.,  i.,  2,  p.  666. 


NARCOTICS  OF  THE  METHANE  SERIES.  127 

The  aldehydes  possess  narcotic  properties,  but  ordinarily  are  irritant  and 
of  disagreeable  odor,  so  that  they  have  not  been  used  in  therapeutics.1  Par- 
aldehyde  (C6H12O3),  a  polymer  of  ordinary  aldehyde,  is,  however,  one  of  the 
newer  hypnotics.  Several  derivatives  of  the  aldehydes  have  been  in- 
troduced, such  as  Methylal  (HCH(OCH8)2)  and  Acetal  (CH3CH(OC2H.)2). 
Another  important  aldehyde  derivative  is  Sulphonal  ( (CH3)2C(SO2C2H5)2), 
which  has  received  considerable  attention  of  late  years  as  a  hypnotic.  Two 
analogous  compounds,  Trional  and  Tetronal,  in  the  first  of  which  one,  in 
the  second  both  methyl  groups  are  replaced  by  ethyl,  are  said  to  be  more 
powerful  than  sulphonal. 

The  only  member  of  the  ketones  which  has  received  attention  at  the  hands 
of  therapeutists,  is  Hypnone  (C6H5COCH3),  which  has  been  used  as  a  hyp- 
notic. 

The  esters,  or  ethereal  salts,  have  been  but  little  used  as  depressants,  and 
seem  to  be  much  weaker  in  action  than  the  corresponding  ethers.2  Some  of 
them,  as  amyl  nitrite,  owe  their  use  not  to  the  action  of  the  alkyl  radicle,  but 
to  the  acid  with  which  it  is  compounded,  and  are  therefore  included  in 
another  group.  One  ester  which  has  been  used  as  a  narcotic  in  therapeutics, 
and  to  a  much  greater  extent  in  animal  experiments,  is  Urethane,  the  ethyl 
ester  of  carbamic  acid  (CO(NH2)(OC2H5)).  Analogous  compounds  recently 
recommended  as  hypnotics  are  Hedonal  (CO(NH2)(OC5Hn) ),  the  carbamic  ester 
of  tertiary  amyl  alcohol,  Veronal,  or  diethylmalonylurea  (  (C2H.)2C(CONH)2 
CO),  and  Neuronal,  or  bromdiethylacetamide  ( (C2H3)2BrC-CONH2). 

The  acids  of  the  methane  series  possess  little  narcotic  action  as  a  general 
rule,  and  have  not  been  used  in  therapeutics  for  this  purpose,  though  butyric 
acid  is  said  to  have  distinctly  depressant  effects  on  the  central  nervous 
system.  When  hydrogen  atoms  of  these  acids  are  replaced  by  chlorine  or 
bromine,  they  acquire  a  much  stronger  action  ;  thus  acetic  acid  is  practically 
devoid  of  narcotic  action,  while  some  of  the  chloracetic  and  bromacetic  acids 
are  narcotic.  But  their  effects  on  the  other  organs  of  the  body  preclude  their 
use  in  therapeutics.3 

Some  of  the  most  important  members  of  this  series  are  halogen  substitution 
products,  formed  by  replacing  one  or  more  atoms  of  hydrogen  in  the  simpler 
substances  of  the  fatty  series  by  chlorine.  This  substitution  often  increases 
the  narcotic  power  to  a  very  great  extent :  methane  (CH4)  is  practically 
not  depressant,  but  if  one,  two,  or  three  of  the  hydrogen  atoms  in  the  molecule 
be  substituted  by  chlorine,  forming  CH3C1,  CH2C12,  and  CHC13,  the  narcotic 
power  increases  with  each  Cl  added.  The  best  known  of  these  is  Chloroform 
(CHC13),  which  is  the  most  powerful  anaesthetic  in  use.  The  analogous  com- 
pounds, Ethylene  Chloride  (CH2C1— CH2C1)  and  Ethylidine  Chloride  (CH3— 
CHC12),  have  fallen  into  disuse,  but  ethyl  chloride  (C2H5C1)  has  recently  been 
recommended  for  short  operations.  Another  important  substitution  product  is 
Chloral,  or  chloral  hydrate  (CC13CH(OH)2),  which  is  the  hydrate  of  trichloral- 
dehyde  (CC13CHO).  An  analogous  compound  is  Butyl  chloral,  or  Croton 
chloral  (C3H4C13CH(OH  )2).  Chloretone  or  Aneson  (trichlorpseudobutylalcohol, 
CC13C(CH3)2OH)  and  Isopral  (trichlorisopropylalcohol,  CC13CHOHCH3)  have 
recently  been  recommended  as  hypnotics. 

Several  compounds  of  chloral  have  been  recently  introduced  into  thera- 
peutics, such  as  Chloralamide  (CC13CHOH — NHCHO),  which  is  a  combina- 
tion of  chloral  with  formamide,  and  Chloralose  (C8HUC13O6),  a  compound  of 
chloral  and  grape  sugar. 

It  has  already  been  mentioned  that  the  substitution  of  chlorine  for  hydro- 
gen in  the  acids  endows  them  with  a  narcotic  effect.  Another  example  of 

1  Formaldehyde  is  used  as  a  disinfectant.     (See  Formalin.) 

2  Vogel,  Pfliiger's  Arch.,  Ixvii.,  p.  141. 

3 Mayer,  Arch.  f.  exp.  Path.  u.  Pharm.,  xxi.,  pp.  97,  119.  Pohl,  ibid.,  xxiv.» 
p.  142. 


128  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

the  alteration  of  the  properties  of  a  substance  by  the  substitution  of  chlorine 
for  hydrogen  is  offered  by  glycerin,  which  in  itself  inert,  becomes  depressant 
to  the  central  nervous  system  when  its  hydroxyl  radicles  are  replaced  by 
chlorine.1 

Some  attempt  has  been  made  to  introduce  bromine  instead  of  chlorine  into 
the  methane  derivatives,  because  bromides  are  central  nervous  depressants, 
and  it  was  hoped  that  a  combination  of  the  methane  and  the  bromide  effects 
could  be  thus  obtained.  But,  as  will  be  explained,  the  bromides  owe  their 
action  to  the  bromide  ion,  which  is  not  present  in  these  organic  compounds. 
Ethyl  bromide  (C2H5Br)  has  been  used  as  an  anesthetic,  and  Bromoform 
(CHBr3)  as  a  narcotic,  but  only  to  a  limited  extent.  The  analogous  com- 
pounds formed  with  iodine  possess  a  powerful  action  which  is  different  from 
that  of  the  other  methane  derivatives,  and  which  precludes  their  use  as  nar- 
cotics. (See  lodoform.) 

The  augmented  effect  of  these  halogen  substitution  derivatives  has  been 
explained  by  reference  to  a  supposed  depressant  effect  of  chlorine  and  bro- 
mine upon  the  brain.  But  even  though  this  were  proved  to  be  the  case,  it 
would  not  elucidate  the  matter,  for  chlorine  is  not  set  at  liberty  in  the 
tissues  when  chloroform  is  inhaled,  the  molecule  acting  as  a  whole.  (See 
page  24.) 

The  chlorine  and  bromine  derivatives  of  methane  are  not  only  more  power- 
ful drugs,  but  also  more  powerful  poisons  than  the  ordinary  compounds  : 
much  less  chloroform  is  required  to  anaesthetize  than  methane,  but  much 
less  is  required  to  kill.  In  addition,  these  compounds,  especially  those  con- 
taining chlorine,  seem  to  have  a  more  powerful  action  on  the  heart  and  cir- 
culation and  on  the  metabolism  than  the  others.  In  other  words,  the  chlo- 
rine bodies  have  a  wider  field  of  activity  and  are  more  nearly  general 
protoplasm  poisons.  (See  Chloroform.) 

All  of  the  narcotics  of  the  methane  series  resemble  each  other  closely 
in  their  general  action.  This  consists  of  a  first  stage  of  imperfect  con- 
sciousness and  confused  ideas,  followed  by  one  of  wild  excitement,  and 
eventually  by  complete  unconsciousness,  which  may  terminate  in  death. 
The  second  stage  is  much  more  marked  after  some  of  the  series  than 
after  others,  and  is  often  entirely  absent.  It  has  given  rise  to  the 
theory  that  these  drugs  stimulate  the  nerve  cells  before  paralyzing 
them,  but  an  alternative  explanation  is  that  the  functions  of  control 
and  inhibition  are  lessened,  and  the  centres  of  motion  are  thus  left  free 
and  act  more  strongly  than  normally.  This  question  has  been  most 
discussed  in  regard  to  alcohol,  and  will  receive  greater  attention  under 
that  heading.  (See  pages  133-135.) 

The  depression  of  the  central  nervous  system  induced  by  these 
bodies  is  in  the  majority  of  cases  accompanied  by  an  alteration  of  the 
circulation  of  the  brain  in  the  direction  of  congestion  or  anaemia,  and 
it  was  formerly  believed  that  these  drugs  induced  depression  by  caus- 
ing anaemia  of  the  brain  and  thus  starving  the  nerve  cells.  But  this 
improbable  explanation  has  been  refuted  by  experiments  in  which  all 
the  blood  of  a  frog  was  replaced  by  salt  solution,  and  the  brain  cells 
thus  deprived  of  nutrition  before  an  anaesthetic  was  applied ;  chloro- 
form then  induced  the  same  changes  as  in  normal  animals.  There  is 
no  question  at  the  present  time  that  these  bodies  act  directly  on  the 

^Marshall  and  Heath,  Jonrn.  of  Physiol.,  xxii.,  p.  38,  and  Kionka,  Arch,  internal, 
de  Pharmacodyn.,  vii.,  p.  475,  give  a  resume  of  the  relation  of  the  chlorine  substi- 
tutes to  the  simple  methane  derivatives. 


ALCOHOL.  129 

nerve  cells,  or  rather  on  the  central  part  of  the  neurons.  Binz  sug- 
gested that  the  change  was  of  the  nature  of  a  coagulation  of  the 
protoplasm,  but  this  theory  is  not  supported  by  microscopic  investiga- 
tion, and  more  recently  histologists  have  been  inclined  to  regard  the  ef- 
fects of  the  central  nervous  depressants  as  associated  with  alterations 
in  the  distribution  of  the  chromatin  in  the  nerve  cells.  A  simple 
explanation  of  nervous  depression  has  been  suggested  in  the  retraction 
of  the  dendrites.  These  finer  processes  of  the  nerve  cells  are  supposed 
to  serve  to  maintain  the  connection  between  the  individual  cells  during 
consciousness  by  forming  ramifications  between  them,  while  it  is  sug- 
gested that  in  natural  sleep  and  in  unconsciousness  in  general,  the  den- 
drites are  withdrawn,  and  the  cells  are  thus  cut  off  from  intercom- 
munication. Some  changes  which  have  been  observed  in  the  dendrites 
after  narcotics  might  be  explained  in  this  way,  but  the  explanation  is 
only  a  hypothesis  at  present.  There  is,  however,  every  probability 
that  the  nerve  cell  depressed  by  drugs  undergoes  changes  similar  to 
those  of  natural  sleep  and  the  changes  in  the  brain  circulation  (anemia) 
may  be  regarded  as  the  result  and  not  as  the  cause  of  the  depression 
in  both  conditions. 

While  the  members  of  this  group  resemble  each  other  closely  in  their 
effects  on  the  central  nervous  system,  they  are  used  for  very  different 
purposes  in  therapeutics  and  may  therefore  be  discussed  in  three  sub- 
groups :  1,  alcohol ;  2,  general  anesthetics,  and  3,  narcotics  or  hyp- 
notics. It  must  be  recognized,  however,  that  there  is  no  hard  and  fast 
line  dividing  these  subgroups ;  for  the  anaesthetics,  chloroform  and 
ether,  may  be  used  in  small  quantities  to  produce  rest  and  sleep,  and 
would  then,  strictly  speaking,  be  narcotics ;  while,  on  the  other  hand, 
chloral  and  sulphonal,  which  are  generally  used  as  hypnotics,  give  rise 
to  complete  anesthesia  when  administered  in  large  quantities. 

I.  Alcohol. 

Ethyl  alcohol  (CH3CH2OH)  has  been  known  in  an  impure  form 
since  the  earliest  times,  and  as  far  back  as  the  history  of  medicine  ex- 
tends, has  been  used  as  a  drug.  Its  medicinal  reputation  has  under- 
gone many  fluctuations,  by  many  held  to  be  a  panacea,  by  others  it 
has  been  considered  of  little  or  no  value  as  a  remedy,  but  of  the 
greatest  importance  as  a  poison. 

Alcoholic  liquors  are  generally  prepared  by  the  fermentation  of 
sugars,  which  either  exist  preformed  in  the  fruits,  or  are  derived  from 
starch  by  a  preliminary  ferment  action.  The  simple  liquors  (wines  and 
beers)  generally  contain  only  a  low  percentage  of  alcohol  (2-20  per 
cent.),  and  the  stronger  preparations  (spirits)  are  prepared  from  them 
by  distillation,  which  raises  the  percentage  to  30—60  per  cent,  and  at 
the  same  time  removes  the  non-volatile  constituents.  Spirits  and 
liquors  are  not,  however,  simple  mixtures  of  alcohol  and  water  but 
contain  many  other  volatile  substances,  the  character  of  which  is  little 
known,  and  which  are  called  oananthic  ethers.  Some  of  them  have 
9 


130  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

been  shown  to  be  higher  members  of  the  alcoholic  series,  while  others 
would  seem  to  be  of  entirely  different  constitution.  The  name  is  de- 
rived from  their  giving  the  odor  and  taste,  or  bouquet,  to  wines. 

Pure  alcohol  is  obtained  from  these  spirits  by  repeated  distillation 
and  by  special  measures  designed  to  remove  the  wrater.  It  is  seldom 
used  in  medicine,  some  form  of  spirits,  wine,  or  beer  being  prescribed 
instead. 

Action. — The  value  of  alcohol  in  medicine  depends  upon  three  chief 
points  :  1,  its  irritant  local  action  ;  2,  its  action  on  the  central  nervous 
system,  and  3,  its  value  as  a  food. 

The  irritant  action  is  not  so  marked  as  that  of  many  other  substances, 
but  is  of  much  greater  importance,  owing  to  the  habitual  use  of  this 
drug.  It  is  probably  due  at  any  rate  in  part  to  the  withdrawal  of 
water  from  the  cells  and  is  shown  by  the  results  of  its  application  to 
the  skin,  to  wounds  and  to  the  mucous  membranes.  Applied  to  the 
skin  in  sufficient  concentration  (e.  g.,  60—90  per  cent.),  it  produces  red- 
ness, itching  and  a  feeling  of  heat  like  other  volatile  and  irritant  sub- 
stances, such  as  the  volatile  oils.  Alcohol  is,  however,  much  less 
irritant  and  at  the  same  time  more  volatile  than  these,  so  that  unless 
its  evaporation  be  prevented,  it  may  produce  a  sensation  of  cold  and 
have  little  or  no  irritant  action ;  this  is  especially  the  case  when  dilute 
alcohol  is  used,  no  very  distinct  appearances  of  irritation  of  the  skin 
being  produced  by  solutions  under  40—50  per  cent.  In  ulcers  and 
other  unprotected  surfaces,  the  irritant  action  is  much  greater  and  the 
cell  division  is  accelerated,  so  that,  judiciously  applied,  it  may  quicken 
the  healing  of  such  breaches  of  continuity.  Concentrated  solutions, 
however,  cause  a  precipitation  of  the  albumins,  and  act  first  as  astrin- 
gents and  later  as  corrosives,  until  they  are  diluted  by  the  fluids  of  the 
wound. 

Its  effects  on  mucous  membranes  are  similar  to  those  on  wounds. 
In  the  mouth  strong  alcohol  produces  a  burning,  unpleasant  sensation 
which  passes  to  the  throat  and  stomach  when  it  is  swallowed,  and  if  the 
concentrated  vapor  be  inhaled,  it  causes  irritation  and  reflex  closure  of 
the  glottis.  The  effects  of  alcohol  on  the  digestive  functions  are  so 
important  that  they  will  receive  further  attention  (page  140), 

The  action  of  alcohol  on  the  Nervous  Centres,  differs  a  good  deal  in 
individuals.  In  small  quantities  it  generally  produces  a  feeling  of 
well-being  and  good-fellowship,  along  with  increased  confidence  in  the 
powers,  mental  and  physical,  of  the  subject  of  the  experiment.  Larger 
quantities  are  followed  by  a  certain  amount  of  excitement,  marked  by 
laughter,  loquacity  and  gesticulation.  The  face  becomes  flushed  and 
hot,  the  eyes  brighter  and  livelier,  the  pulse  is  accelerated.  Even  at 
this  stage  self-control  is  partially  lost  and  the  will  power  is  weakened. 
The  speech  may  be  brilliant,  but  it  often  betrays  the  speaker ;  the 
movements  are  more  lively,  but  they  are  often  undignified.  The  loss 
of  self-control  is  often  indicated  further  by  furious  outbursts  of  anger 
and  unreasonableness,  or  by  the  indulgence  in  maudlin  sentimentality 
and  sensual  fancies.  The  sense  of  responsibility  and  the  power  of 


ALCOHOL.  131 

discrimination  between  the  trivial  and  the  important  are  lost,  and 
the  individual  has  no  regard  for  the  feelings  of  others  or  the  ordi- 
nary conventions  of  life.  If  the  boat  be  further  continued,  the 
movements  become  uncertain,  the  speech  becomes  difficult  and  stam- 
mering, the  walk  becomes  a  stagger,  and  a  torpid  slumber  follows. 
Often  nausea  and  vomiting  set  in,  although  these  are  entirely  absent 
in  some  cases.  On  awaking  from  slumber,  very  great  depression  is 
generally  suffered  from,  together  with  nausea  and  vomiting,  and  want 
of  appetite,  which  may  last  for  several  days  and  is  associated  with  all 
the  symptoms  of  acute  gastric  catarrh. 

Very  large  quantities  of  alcohol  lead  to  a  deep,  torpid  sleep,  which 
eventually  passes  into  total  unconsciousness,  resembling  the  condition 
in  chloroform  anaesthesia ;  the  respiration  becomes  stertorous  and 
slow,  and  the  face,  which  has  hitherto  been  flushed,  becomes  pale  or 
cyanotic.  This  condition  may  last  for  several  hours  and  end  in  death 
from  failure  of  the  respiration,  but  in  other  cases  the  anaesthesia  be- 
comes less  deep,  and  after  a  very  prolonged  sleep  the  patient  recovers. 
When  the  stage  of  anaesthesia  is  reached,  it  lasts  very  much  longer 
than  that  produced  by  chloroform  and  ether.  It  is  said  that  persons 
rarely  or  never  recover  if  unconsciousness  lasts  longer  than  10—12 
hours  after  the  drinking  bout. 

The  effects  of  alcohol  vary  greatly,  however,  in  different  individ- 
uals and  in  the  same  individual  at  different  times.  One  person  is 
rendered  sentimental,  another  bellicose,  while  in  a  third  there  may  be 
no  appearance  of  excitement,  the  first  distinct  symptom  being  pro- 
found slumber.  When  drinking  is  indulged  in  in  company,  the  excite- 
ment stage  is  a  very  common  phenomenon,  but  if  alcohol  is  taken 
without  the  exhilarating  accompaniments  of  bright  lights  and  exciting 
companionship,  it  is  much  less  frequently  seen,  and  the  question  has 
therefore  arisen  how  far  the  environment  produces  the  excitement  in 
alcoholic  intoxication. 

It  may  be  stated  at  once  that  there  exist  two  distinct  views  as  to  the 
action  of  alcohol  on  the  central  nervous  system  :  the  one  stoutly  upheld 
by  Binz  and  his  pupils,  that  alcohol  first  stimulates  and  then  depresses 
the  nerve  cells ;  the  other  championed  by  Schmiedeberg,  Bunge  and 
their  followers,  that  it  depresses  the  central  nervous  system  from  the 
beginning.  The  symptoms  of  excitement  require  no  explanation  on 
the  first  theory,  which  is  rather  to  be  looked  on  as  the  natural  expres- 
sion of  the  facts  observed.  On  the  other  hand,  Schmiedeberg  ex- 
plains them  as  not  due  to  true  stimulation  of  the  motor  areas,  but 
as  the  result  of  these  areas  being  freed  from  control  by  the  weakening 
of  the  highest  functions  of  the  brain  —  the  will  and  self-restraint. 
Even  the  smallest  quantities  of  alcohol  tend  to  lessen  the  activity  of 
the  brain,  the  drug  appearing  to  act  most  strongly,  and  therefore  in  the 
smallest  quantities,  on  the  most  recently  acquired  faculties,  to  anni- 
hilate those  qualities  that  have  been  built  up  through  education  and 
experience,  the  power  of  self-control  and  the  sense  of  responsibility. 

The  question  is  a  most  difficult  one  to  decide,  for  on  the  one  hand  it 


132  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

has  been  shown  that  the  simplest  movement  is  the  result  of  a  combi- 
nation of  motor  and  inhibitory  impulses  from  the  brain,  while  on  the 
other  hand  the  measurement  of  the  relative  strength  of  these  impulses 
is  one  of  the  most  difficult  problems  of  biology.  The  advocates  of  the 
stimulant  action  point  to  the  confidence  in  their  own  powers  exhibited 
by  intoxicated  persons,  to  the  brilliancy  of  the  after-dinner  speech,  and 
to  the  excitement  stage  as  evidences  of  the  increased  activity  of  the 
brain.  But  their  opponents  question  whether  the  confidence  is  accom- 
panied by  any  really  increased  physical  strength,  and  point  out  that 
the  brilliancy  of  speech  may  be  due  to  the  environment  and  to  the 
speaker  having  lost  his  habitual  shyness  and  nervousness,  and  that  the 
excitement  is  generally  absent  when  the  associations  are  different,  or 
degenerates  into  a  form  which  more  distinctly  resembles  depression. 

More  definite  evidence  for  or  against  the  stimulant  action  of  alcohol 
has  therefore  been  sought  by  comparing  the  amount  of  work  which 
can  be  done  with  and  without  it;  and  an  apparent  confirmation  of 
Bunge's  view  has  been  found  in  the  results  of  the  use  of  alcohol  by 
troops  on  the  march,  for  repeated  experience  has  shown  that  those  regi- 
ments which  were  not  supplied  with  alcohol  marched  farther  and  were 
in  better  condition  at  the  end  of  the  day  than  others  to  which  it  had 
been  given.  Forms  of  work  requiring  larger  drafts  upon  the  intel- 
ligence than  the  marching  of  soldiers  are  also  performed  less  correctly 
with  alcohol  than  without  it ;  thus  typesetters  can  do  more  work  and 
make  fewer  errors  when  they  abstain  from  its  use.  The  capacity  for 
work  depends  not  so  much  upon  the  actual  strength  of  the  muscles  as 
upon  the  condition  of  the  brain,  and  these  experiments  are  therefore 
generally  quoted  as  evidence  of  the  depressant  action  of  alcohol. 
Their  results  are  not  incompatible  with  the  view  that  alcohol  primarily 
stimulates  the  nerve  cells,  however,  for  Binz  and  his  followers  allow 
that  the  stimulation  is  transient  and  is  followed  by  depression,  and  if 
a  sufficient  time  elapse  after  the  alcohol  is  taken,  the  stage  of  depres- 
sion is  elicited  and  the  total  work  may  thus  be  reduced.  A  more  exact 
method  of  examining  the  initial  effects  of  alcohol  on  work  is  afforded 
by  measuring  at  different  intervals  after  the  drug  is  given  the  work  of 
which  a  muscle  is  capable  before  it  is  completely  fatigued.  This  has 
been  done  in  a  number  of  experiments  with  the  ergograph  and  the 
dynamometer,  which  have  not  all  given  the  same  result ;  the  majority 
of  the  investigators  hold,  it  is  true,  that  the  initial  effect  of  small 
quantities  is  to  increase  the  capacity  for  work,  but  this  effect  is  a  tran- 
sient one  and  is  quickly  followed  by  a  marked  loss  of  power  (Hellsten)  ; 
in  fatigue  the  stimulating  effect  is  much  more  evident  than  in  untired 
muscles,  and  all  observers  are  agreed  that  only  the  smallest  quantities 
elicit  this  action.  The  interpretation  of  the  observation  is  disputed, 
some  regarding  the  initial  increase  of  capacity  as  evidence  of  transient 
cerebral  stimulation,  others  attributing  it  to  the  alcohol  acting  as  a 
muscle  food  or  affecting  the  peripheral  nerves. 

The  measurement  of  intellectual  work  is,  of  course,  much  more 
difficult,  and  the  results  are  very  liable  to  misinterpretation,  but 


ALCOHOL.  133 

Kraepelin  found  in  a  series  of  careful  measurements  of  the  simpler 
cerebral  processes  that  the  receptive  and  intellectual  powers  were  weak- 
ened by  very  small  quantities  of  alcohol,  while  the  motor  functions 
seemed  to  be  facilitated  by  small,  and  retarded  by  large  quantities. 
For  example,  a  person  under  even  a  small  dose  of  alcohol  makes  more 
errors  than  usual  in  adding  a  row  of  figures  and  in  reading  a  series  of 
unconnected  syllables,  and  apparently  recognizes  letters  and  words 
somewhat  more  slowly.  It  is  interesting  to  find  that  the  subject  of  the 
experiment  is  quite  unaware  of  the  inferiority  of  his  work  and  is  often 
persuaded  that  it  is  unusually  good.  Kraepelin's  latest  investigations 
tend  to  show  that  this  effect  of  alcohol  lasts  much  longer  than  is  gen- 
erally recognized,  the  mental  equilibrium  being  reinstated  only  12-24 
hours  after  even  very  moderate  indulgence  in  alcohol.  He  leans  to 
the  view  that  alcohol  weakens  and  paralyzes  some  parts  of  the  brain, 
while  primarily  stimulating  others,  but  brings  forward  no  new  evidence 
that  this  stimulation  is  not  fictitious  and  really  due  to  the  removal  of 
the  barriers  of  self-restraint  by  the  paralysis  of  higher  areas.  Jacob] 
found  that  small  differences  in  weight  could  be  estimated  more  correctly 
under  alcohol  than  in  the  normal  condition  of  the  brain,  and  this  would 
seem  at  first  sight  to  indicate  primary  stimulation,  but  he  believes  that 
the  true  explanation  is  a  retardation  of  the  cerebral  processes.  The 
sensation  of  pain  is  also  found  to  be  lessened  by  even  small  quantities 
of  alcohol.  No  unequivocal  evidence  of  the  initial  stimulant  action  on 
the  brain  has  yet  been  adduced,  for  each  new  feature  may  be  inter- 
preted as  really  due  to  the  depression  of  controlling  or  inhibitory  func- 
tions. Of  course,  there  is  no  absolutely  convincing  proof  that  no 
stimulation  of  the  motor  areas  occurs,  and  no  physiological  proof  of 
the  existence  even  of  controlling  areas  can  be  adduced,  much  less  of 
their  paralysis  by  alcohol.  Ou  the  other  hand,  no  other  known  drug 
stimulates  the  motor  areas  only,  without  increasing  the  activity  of  the 
lower  parts  of  the  system  at  some  stage  of  its  action,  and  the  advocates  of 
the  stimulant  action  have  to  consider  chloroform  and  ether  also  brain 
stimulants,  for  they  cause  a  stage  of  excitement  very  similar  to  that  pro- 
duced by  alcohol,  and,  in  fact,  have  been  used  as  habitual  intoxicants. 

Acute  alcoholic  intoxication  leads  to  very  distinct  alterations  in  the  histo- 
logical  appearance  of  the  cells  of  the  central  nervous  system,  which  have 
been  described  by  Dehio,  Stewart  and  others.  The  chief  change  noted  by 
them  consists  in  replacement  of  the  chromatin  network  by  fine  granules, 
which  in  turn  seem  to  become  dissolved  in  the  general  cytoplasm.  Staining 
reagents,  therefore,  give  rise  to  a  diffused  coloration  of  the  cell  rather  than 
to  localized  masses  of  color,  such  as  are  seen  in  the  normal  cell.  The  den- 
drites  are  shortened  and  exhibit  rounded  nodosites  along  their  course. 

In  the  lower  parts  of  the  central  nervous  system  the  evidences  of 
primary  depression  are  less  open  to  question.  For  example,  the  coor- 
dination of  the  movements  suffers  at  an  early  stage  in  alcohol  drink- 
ing, long  before  the  generally  recognized  forms  of  lack  of  coordination, 
such  as  indistinct  speech  and  staggering,  appear.  In  the  spinal  cord 
alcohol  causes  a  depression  of  the  reflex  irritability,  which  passes  into 
complete  paralysis  some  time  before  the  respiration  ceases. 


134  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

The  medulla  oblongata  is  the  last  part  of  the  central  nervous  system 
to  be  acted  on  by  alcohol,  or  at  any  rate  to  undergo  complete  pa- 
ralysis.    The  Respiratory  and  Circulatory  Centres  preserve  their  func- 
tions long  after  the  occurrence  of  complete  unconsciousness  and  the 
disappearance  of  the  ordinary  reflexes.     The  same  question  has  been 
raised  in  regard   to  the   respiratory  centre,  as  has  been  already  dis- 
cussed in   the  consideration  of  the  brain,  and  the  same  two  opposing 
views  have  been  upheld.     These  are  of  greater  importance  as  regards 
the  respiratory  centre,  because  the  advocates  of  the  stimulation  theory 
advise  the  use  of  alcohol   in  conditions  of  the  respiration  in  which 
it  is  directly  contraindicated  if  the  other  view   be  the  correct  one. 
The  question  here  is  apparently  much  more  simple,  because  the  ac- 
tivity of  the  respiratory  centre  can  be  estimated  directly  by  measuring 
the  number  of  the  respirations  and  the  amount  of  air  inhaled  during 
each ;  but  a  large  number  of  such  experiments  .have  been  performed 
with  very  varying  results.      If   the    number  of  the  respirations  be 
counted  in  a  person  in  the  excitement  stage  of  alcoholic  intoxication, 
it  is  often  found  to  be  much  greater  than  normally,  but  this  may  be 
due  to  the  muscular  movements  and  need  not  indicate  any  direct  action 
of  the  drug  on  the  medullary  centre.     And,  of  course,  this  excitement 
stage  is  not  elicited  in  therapeutics,  and  the  value  of  alcohol  as  a  res- 
piratory stimulant  must  therefore  be  estimated  in  cases  in  which  no 
such  excitement  is  caused.     A  number  of  such  estimations  have  been 
made  in  man  and  animals,  and  on  the  whole  the  evidence  shows  that 
in  man  even  when  no  excitement  is  produced  and  in  some  instances 
even  when  sleep  follows,  the  amount  of  air  inhaled  is  larger  than  before 
the    drug    was    administered    (Jaksch,    Zuntz  and  Berdez,   Geppert, 
Weissenfeld,  Wendelstadt) ;    the   increase    is  generally  more  evident 
when   alcohol   is   taken   during  fatigue  and  exhaustion  than   in   ordi- 
nary   conditions.     This    may    not    indicate    a    direct    stimulation    of 
the  respiratory  centre,  however,  for  the  increase  is  often  not  greater 
than  that  following  an   ordinary  meal,  and  may  therefore  be  attrib- 
uted to  the  respiratory  centre  being  indirectly  affected  by  the  activity 
of  the   stomach   and   intestine.     And   it  is  to  be  noted  that  alcohol 
may  have  more  indirect  effect  on  the  respiration  than  ordinary  food 
because   it   is   so   much   more   irritant   to  the   stomach   wall.     These 
experiments  failing  to   determine   whether   the    respiratory   centre    is 
directly   stimulated  in  man,  another  method  has  been  employed   by 
Loewy  in  which  the  excitability  of  the   centre  was  estimated   by  its 
response  to  the  stimulus  of  an  increase  of  the  carbonic  acid  in  the 
blood.     Unfortunately,  his   experiments   were   too   few  to   permit  of 
general  inferences,  but  they  lend  no  support  to  the  theory  that  the 
irritability  of  the  centre  is  increased.     There  is  therefore  no  sufficient 
evidence  that  the  respiratory  centre  is  directly  stimulated  in  man  and 
the  increase  in  the  amount  of  air  inhaled  may  be  due  to  the  peripheral 
action  of  alcohol. 

In  the  dog,  no  acceleration  of  the  respiration  occurs  after  alcohol,  while 
in  the  rabbit,  on  the  other  hand,  the  respiration  is  much  accelerated,  and 


ALCOHOL.  135 

the  amount  of  air  inhaled  shows  a  corresponding  increase.  Jacquet  has 
attempted  to  show  that  this  is  due  to  the  local  action  of  the  alcohol,  and  not 
to  any  direct  effect  on  the  nervous  sytem,  but  his  results  have  been  disputed 
by  VVilmanns ;  Singer  also  refuses  to  recognize  the  changes  in  the  rabbit's 
respiration  as  an  indication  of  direct  action  on  the  respiratory  centre  and  is 
disposed  to  attribute  them  to  the  irritation  of  the  stomach  and  the  increased 
muscular  activity  which  is  rendered  necessary  by  the  loss  of  heat  entailed 
by  the  dilatation  of  the  cutaneous  blood  vessels. 

In  short,  there  is  no  unequivocal  evidence  that  the  increase  in  the  respi- 
ration under  alcohol  in  health  is  due  to  direct  stimulation  of  the  respiratory 
centre,  while  on  the  other  hand,  no  depression  of  the  activity  of  this  centre 
occurs  except  at  a  late  stage  of  alcohol  poisoning.  Alcohol  is  often  said  to 
slow  the  respiration  in  fever  patients  and  to  stimulate  it  in  cases  of  shock. 
In  the  first  case,  however,  there  need  be  no  direct  action  on  the  respiratory 
centre,  for  it  seems  much  more  likely  that  the  improvement  (when  present 
at  all)  is  due  to  the  alcohol  lessening  the  excitement  through  its  narcotic 
action.  The  pathology  of  shock  is  so  little  understood  that  it  would  be  use- 
less to  attempt  to  explain  its  therapeutics,  but  if,  as  is  held  by  many,  shock 
is  a  condition  of  great  inhibitory  activity,  the  action  of  alcohol  may  be 
explained  by  its  depressant  effects,  while  on  the  other  hand,  it  is  difficult  to 
explain  these  two  contradictory  effects  on  the  theory  that  alcohol  is  a 
stimulant. 

The  whole  question  might  be  supposed  to  possess  merely  theoretical 
interest ;  in  cases  in  which  the  respiration  is  insufficient  it  would  seem 
that  it  is  of  little  moment  whether  it  is  improved  by  a  direct  increase 
in  the  activity  of  the  centre,  or  by  some  peripheral  action.  This  is 
not  correct,  however,  for  if  the  respiration  is  increased  only  to  cope 
with  the  products  of  the  augmented  activity  of  the  alimentary  tract, 
the  general  economy  may  profit  little.  On  the  other  hand,  if  the  air 
inspired  is  augmented  in  a  greater  ratio  than  these  products,  as  is  the 
case  when  the  centre  is  directly  stimulated,  the  advantage  to  the  organ- 
ism is  correspondingly  great. 

The  action  of  alcohol  on  the  Circulation  is  no  less  disputed  than  that 
on  the  respiration,  and  the  same  divergence  exists  in  the  statements  of 
the  supporters  of  the  stimulation  theory.  The  real  foundation  for  this 
view  is  here  again  the  acceleration  of  the  pulse  during  the  excitement 
of  alcoholic  intoxication,  which  may  be  due  to  the  increased  muscular 
effort  and  not  to  any  direct  action  on  the  heart.  Jacquet  has  shown 
that  the  pulse  rate  is  unaltered  by  alcohol  in  normal  cases,  provided 
that  no  excitement  be  produced  by  the  environment.  In  animals 
alcohol  has  no  effect  on  the  pulse  rate,  unless  given  in  very  large  quan- 
tities, when  it  produces  effects  similar  to  those  described  under  chloro- 
form and  ether  —  weakening  of  the  auricular  systole,  and  later  of  the 
ventricular,  with  distention  of  both  cavities  and  slowing.  The  effects 
of  alcohol  on  the  heart  are,  however,  very  much  less  marked  than 
those  of  chloroform,  for  Dieballa  found  that  48  times  as  much  alcohol 
as  chloroform  was  required  to  modify  the  movements  of  the  frog's 
heart,  and  that  in  order  to  bring  it  to  a  standstill  192  times  as  much 
alcohol  was  required.  Loeb  has  recently  shown  that  the  cat's  heart 
continues  to  beat  strongly  when  a  2  per  cent,  solution  of  alcohol  is 
perfused  through  the  coronary  vessels.  Alcohol  having  been  shown 


136  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

FIG.  2. 


Tracing  of  the  dog's  ventricle  under  alcohol.  8  c.c.  (2  drs. )  of  50  per  cent,  alcohol  were  injected  into 
a  vein  during  this  tracing,  but  no  effect  whatever  is  visible  in  the  movement  of  the  heart.  Du ring- 
systole  the  lever  moves  upwards,  during  diastole  downwards.  (The  tracing  is  to  be  followed  from 
left  to  right.) 

FIG.  3. 


Tracing  of  the  movements  of  the  ventricle  (lower)  and  auricle  (upper)  of  the  dog  when  a  large  dose 
(20  c.c.  or  %  oz. )  of  50  per  ceut.  alcohol  is  suddenly  thrown  into  a  vein.  The  levers  move  upwards 
during  systole,  downwards  during  diastole.  A,  normal.  Bt  injection.  The  systole  of  the  auricle  is 
very  much  weakened,  the  diastole  is  less  affected.  The  ventricular  systole  is  comparatively  little 
changed,  although  it  also  is  a  little  weaker.  The  effect  passes  off  very  rapidly,  so  that  at  the  end  of 
the  tracing  both  chambers  have  almost  recovered.  A  very  similar  effect  is  seen  under  chloroform. 
(Fig.  9.)  (The  tracing  is  to  be  followed  from  right  to  left.) 


ALCOHOL.  137 

not  to  increase  the  rate  of  the  heart,  its  advocates  have  begun  to  state  that 
the  force  of  the  contraction  is  augmented,  without,  however,  bringing 
forward  any  evidence  of  this  worthy  of  attention.  In  animal  experi- 
ments it  has  been  shown  that  the  first  effect  of  alcohol  on  the  heart  is 
lessened  efficiency  and  weakness  of  the  contractions.  (Figs.  2  and  3.) 

The  flushing  of  the  skin  which  occurs  in  alcoholic  intoxication  would 
seem  to  point  to  some  vascular  action,  but  it  is  impossible  to  say  at 
present  what  the  nature  of  this  action  is.  It  indicates  dilation  of  the 
skin  vessels,  but  whether  this  is  of  central  or  peripheral  origin,  whether 
due  to  stimulation  of  dilator  centres  or  paresis  of  vaso-constrictors,  is 
unknown.  The  widening  of  the  blood  path  through  this  dilation  is 
but  slight,  and  produces  little  or  no  fall  in  the  general  blood-pressure. 
Very  large  quantities  of  alcohol  cause  a  marked  fall  in  the  arterial 
tension,  through  weakening  the  vaso-constrictor  centres  and  the  heart 
muscle,  but  the  quantities  of  alcohol  required  to  cause  any  great  fall 
in  blood-pressure  are  far  in  excess  of  those  used  in  therapeutics.  It 
has  been  suggested  that  the  widening  of  the  arteries  may  in  itself 
relieve  the  heart  by  lessening  the  resistance  against  which  it  has  to  con- 
tract, but  it  has  yet  to  be  proved  that  any  marked  dilation  of  the  vessels 
occurs  before  the  direct  action  on  the  heart  muscle.  Some  evidence  of 
this  is  forthcoming,  it  is  true,  for  Hammeter  found  the  velocity  of  the 
blood  current  increased  by  alcohol,  but  he  does  not  state  the  quantity 
used  in  his  experiments. 

The  slowing  of  the  heart  which  often  follows  the  administration  of 
alcohol  in  fever,  would  seem  due  rather  to  its  diminishing  the  cerebral 
excitement  than  to  its  direct  action  on  the  heart.  On  the  other  hand, 
the  alleged  improvement  of  the  circulation  in  shock  may  be  due  to  a 
reflex  from  the  irritant  local  action,  and  certainly  would  not  seem  to 
require  any  direct  cardiac  action  for  its  explanation. 

Alcohol  has  little  effect  on  Muscle  or  on  peripheral  Nerves  when  it  is  carried 
to  them  by  the  blood,  but  Lee  states  that  frog's  muscle  is  stimulated  by  small 
quantities  and  weakened  by  larger  amounts.  When  a  frog's  nerve  is  exposed  to 
alcoholic  vapor  its  irritability  is  first  increased  and  later  diminished  if  the 
quantity  applied  be  large  enough.  This  fact  has  been  used  by  Scheffer  to  explain 
the  results  of  ergographic  experiments  in  which  the  amount  of  work  done  under 
alcohol  is  at  first  augmented.  He  regards  this  augmentation  as  due  not  to  central 
stimulation,  but  to  the  peripheral  processes  being  facilitated.  The  sensory 
fibres  are  said  to  be  depressed  before  the  motor. 

The  eifect  of  alcohol  on  the  Digestion  has  been  the  subject  of  many  in- 
vestigations, both  from  the  clinical  and  the  experimental  point  of  view. 
There  exists  a  widespread  belief  in  both  lay  and  medical  circles  that 
small  quantities  of  alcohol  taken  before  a  meal  increase  the  appetite, 
while  after  food  they  accelerate  the  digestion.  It  is  obvious  that 
alcohol  may  aifect  digestion  either  by  altering  the  activity  of  the  fer- 
ments in  the  digestive  canal,  or  by  altering  the  secretion,  movement, 
or  absorption  of  the  stomach  and  intestine.  The  digestive  power  of 
the  ferments  outside  the  body  has  been  found  to  be  unaltered  or 
slightly  increased  when  alcohol  is  present  in  very  small  quantity.  In 


138  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

a  solution  of  5—10  per  cent,  of  alcohol  or  of  spirits,  however,  the  gas- 
tric juice  digests  very  much  more  slowly  than  normally,  and  the  pan- 
creatic secretion  is  affected  prejudicially  by  even  smaller  quantities. 
(Chittenden  and  Mendel.)  Very  large  quantities  of  alcohol  precipitate 
the  proteids,  but  it.  is  unlikely  that  sufficient  alcohol  to  produce  this 
effect  ever  remains  in  the  stomach  for  any  length  of  time.  The  malt 
liquors  and  wines  are  much  more  detrimental  to  the  digestive  ferments 
than  pure  alcohol  or  spirits,  and  the  augmentation  of  the  activity  of  the 
ferments  is  so  slight  in  any  case  that  it  does  not  seem  likely  that  it 
plays  any  important  role  in  the  effects  of  alcohol  on  the  stomach. 

The  presence  of  alcohol  in  the  mouth  causes  (according  to  Chitten- 
den, Mendel  and  Jackson)  a  very  appreciable  increase  in  the  secretion 
of  the  saliva,  presumably  by  reflex  action.  As  regards  the  action  on 
the  stomach  wall,  it  is  to  be  remembered  that  alcohol,  even  in  compar- 
atively dilute  solution,  is  an  irritant,  and  therefore  leads  to  increased 
activity  of  the  cells,  a  more  active  circulation  in  the  organ,  and  prob- 
ably to  a  more  rapid  secretion  of  both  acid  and  solids  of  the  gastric 
juice.  But  apart  from  this  local  action  on  the  stomach,  it  appears  to 
exert  a  specific  action  on  the  secretion  after  its  absorption  into  the  cir- 
culation. For  when  it  is  injected  into  the  dog's  rectum,  a  profuse 
secretion  from  the  gastric  mucous  membrane  follows,  and  when  part  of 
the  stomach  is  isolated  from  the  rest  of  the  organ,  so  that  alcohol  given 
by  the  mouth  fails  to  enter  it,  this  part  still  shares  in  the  secretion. 
According  to  Radzikowski,  the  pepsin  secretion  is  not  always  cor- 
respondingly augmented,  the  alcohol  not  accelerating  the  formation  of 
pepsin  from  propepsin  but  merely  leading  to  the  secretion  of  the  pepsin 
preformed  in  the  cells.  Similar  effects  have  been  obtained  in  man  by 
Spiro,  who  administered  alcohol  by  the  rectum.  It  has  been  further 
demonstrated  that  the  absorption  of  fluids  from  the  stomach  and  bowel 
is  much  accelerated  by  the  addition  of  alcohol  (Brandl,  Scanzoni,  Farn- 
steiner,  Tappeiner),  and  the  movements  of  the  stomach  are  also  aug- 
mented by  moderate  quantities.  (Klemperer,  Batelli.) 

Digestion  in  the  stomach  may  thus  be  influenced  in  two  opposite  di- 
rections when  alcohol  is  administered  in  the  usual  form  of  wine,  spirits, 
or  beer.  The  action  on  the  ferments  is  deleterious  while  the  changes 
in  the  stomach  wall,  the  increased  secretion  and  movement  and  the 
accelerated  absorption,  are  beneficial  in  many  cases.  These  two  opposing 
factors  may  neutralize  each  other,  as  in  the  dog  in  which  the  rate  of  diges- 
tion is  scarcely  altered,  the  retarding  effects  of  alcohol  on  the  proteolysis 
being  compensated  for  by  the  more  abundant  secretion  of  the  juice, 
which  continues  after  the  alcohol  is  absorbed,  and  therefore  after  its 
deleterious  effects  on  the  fermentation  have  disappeared.  (Chittenden, 
Mendel  and  Jackson.)  In  man  the  result  varies,  the  one  factor  pre- 
dominating in  some  cases,  the  other  in  others.  Thus,  while  Kretschy 
and  Buchner  found  that  the  digestion  of  proteids  in  the  human  stomach 
was  distinctly  retarded  by  alcohol  and  beer,  Eichenberg,  Wolffhardt 
and  others  state  that  small  quantities  of  alcohol  or  wine  accelerate  the 


ALCOHOL.  139 

digestion,  and  Gluzinsky  came  to  the  conclusion  that  as  long  as  alcohol 
remains  in  the  stomach  the  digestion  is  retarded,  but  that  after  its  ab- 
sorption the  digestion  progresses  more  rapidly  than  if  no  alcohol  had 
been  given.  Zuntz  and  Magnus-Levy  have  shown  that  the  addition  of 
beer  to  the  dietary  does  not  affect  the  absorption  and  utilization  of  the 
food  by  the  tissues.  It  is  not  unlikely  that  the  taste  has  some  influ- 
ence on  the  result,  that  in  those  who  enjoy  the  taste  of  alcohol,  it  in- 
duces a  more  rapid  secretion  and  an  improved  digestion,  while  in  those 
to  whom  it  is  disagreeable,  the  secretion  is  less  altered. 

The  divergence  of  opinion  exists  only  in  regard  to  the  effects  of 
small  quantities,  for  all  are  agreed  as  to  the  deleterious  action  of  any 
but  moderate  doses  of  alcohol  on  the  digestion.  After  large  quantities 
the  irritation  of  the  stomach  wall  is  so  great  that  nausea  and  vomiting 
are  induced.  There  is  every  reason  to  suppose  that  this  is  due  to  the 
local  irritation,  and  not  to  the  action  of  the  absorbed  alcohol  on  the 
nervous  centres.  A  large  dose  of  concentrated  alcohol  sometimes 
leaves  evidence  of  its  irritant  action  in  redness  and  injection  of  the 
mucous  membrane  and,  it  is  said,  in  ecchymoses,  but  in  most  cases 
of  fatal  poisoning  no  such  appearances  are  to  be  observed  after 
death. 

Is  Alcohol  a  Food  ?  —  This  has  long  been  discussed,  and  that  with 
more  passion  and  prejudice  than  are  generally  elicited  by  pharmacolog- 
ical questions.  It  was  formerly  supposed  that  the  alcohol  absorbed 
from  the  stomach  was  excreted  unchanged  by  the  lungs,  skin  and 
kidneys,  and  therefore  gave  up  no  energy  to  the  body  in  its  passage 
through  it.  But  it  has  been  shown  that  only  the  small  amount  of 
from  5—10  per  cent.1  of  the  ingested  alcohol  is  really  excreted  in  this 
way,  and  that  mainly  by  the  kidneys  and  lungs,  the  skin  taking  prac- 
tically no  part  in  the  excretion.  The  rest  of  the  alcohol  absorbed 
from  the  stomach  and  bowel,  amounting  to  over  90  per  cent.,  undergoes 
combustion.  The  fact  that  none  of  the  products  of  the  combustion 
have  been  isolated  from  the  body  does  not  invalidate  this  statement, 
for  the  corresponding  products  of  sugar  are  not  known,  but  there  is  no 
doubt  that  sugar  is  oxidized  in  the  body.2  According  to  Grehant's 
recent  work,  the  oxidation  of  alcohol  progresses  slowly,  appreciable 
amounts  being  found  in  the  blood  twenty -four  hours  after  its  ingestion  ; 
this  accords  with  Kraepelin's  statement  that  its  effect  on  the  brain  can  be 

1  Kecent  investigations  suggest  that  even  this  is  too  high  a  valuation  tor  the  alcohol 
excreted  and  that  only  2-3  per  cent,  of  that  ingested  escapes  oxidation.  In  particular 
there  seems  reason  to  question  whether  anything  more  than  traces  escape  by  the  lungs. 
A  very  small  quantity  appears  in  combination  with  glycuronic  acid  in  the  urine  of 
some  animals,  notably  the  rabbit. 

2 It  has  been  suggested  that  the  oxidation  of  alcohol  in  the  body  may  not  give  rise 
to  the  same  products  as  its  oxidation  in  the  chemical  laboratory.  If  aldehyde  were 
formed  it  would  be  excreted  in  part  by  the  lungs  and  kidneys,  for  aldehyde  injected 
into  the  blood  at  once  appears  in  the  breath  and  urine.  Acetic  acid  has  never  been 
identified  with  certainty  after  alcohol,  but  formic  acid  is  excreted  after  methyl  alcohol, 
and  it  therefore  seems  probable  that  ethyl  alcohol  is  oxidized  to  acetic  acid  immediately, 
and  that  this  at  once  undergoes  further  decomposition. 


140  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

detected  for  12-24  hours.  In  undergoing  combustion  alcohol  gives  up 
energy  to  the  body,  and  therefore  is  technically  a  food.  This  statement 
has  met  with  a  great  deal  of  opposition,  and  the  mere  fact  that  alcohol 
gives  up  energy  to  the  body  does  not  constitute  it  an  advisable  food  in 
all  conditions.  For  example,  the  question  might  be  raised  whether 
alcohol  does  not  require  an  amount  of  energy  for  its  absorption  equal 
to  that  liberated  by  its  combustion,  or  whether  its  action  on  the  nervous 
centres  does  not  produce  a  greater  waste  of  force  than  the  food  itself 
supplies.  Both  of  these  have  been  answered  by  experiments  in  which 
the  carbonic  acid  excretion  of  the  body  has  been  measured  before  and 
after  alcohol.  Zuntz  and  Berdez  and  Geppert  have  shown  by  this 
method  that  after  alcohol  is  taken,  a  slight  rise  of  5—10  per  cent,  occurs 
in  the  output  of  carbonic  acid ;  that  is,  a  small  amount  of  extra  com- 
bustion goes  on,  a  certain  amount  of  energy  is  required  for  the  absorp- 
tion, but  this  is  not  greater  than  that  required  for  the  absorption  of 
any  other  form  of  food.  And  the  total  amount  of  carbonic  acid  ex- 
creted in  24  hours  is  not  appreciably  altered  by  alcohol,  so  that  alcohol 
taken  in  addition  to  the  ordinary  food  is  either  itself  transformed  into 
tissue,  or  undergoes  oxidation  instead  of  some  substance  which  in  turn 
is  used  to  build  up  the  body.  Strassmann  has  shown  that  animals  that 
receive  alcohol  tend  to  lay  on  more  fat  than  others  receiving  the  same 
food  without  alcohol,  and  this  is  in  accord  with  the  common  observa- 
tion of  the  obesity  of  alcohol  drinkers.  Alcohol,  therefore,  acts  as  a 
substitute  for  fats  and  carbohydrates  in  the  food  to  some  extent. 

It  has  long  been  recognized  that  when  insufficient  fat  and  carbohy- 
drate is  supplied  to  the  body,  the  proteids  are  drawn  upon  to  make 
good  the  deficiency  and  the  nitrogen  eliminated  rises  accordingly.  On 
the  other  hand,  when  the  fats  and  carbohydrates  of  the  food  are  in- 
creased, the  organism  economizes  its  proteid  and  the  nitrogen  tends  to 
fall.  This  is  the  most  accurate  method  of  testing  the  food  value  of 
non-nitrogenous  substances,  and  alcohol  has  been  the  subject  of  a  num- 
ber of  such  investigations.  The  divergent  results  have  given  rise  in 
the  last  few  years  to  a  series  of  experiments  which  promise  to  become 
classical  for  the  extraordinary  patience  and  conscientiousness  exhibited 
by  those  engaged  in  them  as  well  as  for  the  complete  agreement  in  the 
results  obtained  by  investigators  who  approached  the  subject  with 
opinions  which  were  diametrically  opposed.  These  experiments,  which 
may  be  cited  as  models  of  investigations  in  metabolism,  were  performed 
by  Neumann,  Atwater  and  Benedict,  and  Rosemann  and  his  pupils. 
The  results  may  best  be  illustrated  by  an  account  of  Neumann's 
first  experiment. 

This  lasted  35  days  divided  into  six  periods.  The  proteids  of  the 
food  and  the  carbohydrates  remained  constant  throughout  while  alcohol 
was  substituted  for  part  of  the  fat  for  some  time  (see  Fig.  4).  Dur- 
ing the  first  five  days,  the  nitrogen  excreted  was  practically  equal  to 
that  of  the  food  (nitrogenous  equilibrium),  while  during  the  next  four 
days  one  half  of  the  fat  of  the  food  was  omitted  and  the  immediate  result 


ALCOHOL. 


141 


was  an  increase  in  the  nitrogen  excreted,  indicating  that  the  proteids  of 
the  body  were  being  drawn  upon  to  make  good  the  deficit  in  the  fat  of 


FIG.  4. 


DAYS 
PERIODS 

FAT  OF 

FOOD 

ALCOHOL 
NITROGEN 

1 

•> 

sk 

.i 

i; 

- 

8 

9 

Id 

11 

12 

ir: 

n|lo 

16 

17 

IS 

19 

20 

a 

2223 

_>i 

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<r, 

27|28 

j-.i 

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:U 

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u  '.0 

I 

i 

I 

III 

I 

V 

^ 

f 

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I 

I 

; 

i;C 

: 

1 
i 

_> 

vi 

;';; 

I 

^ 

0. 

I 

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i 

56 

o 

DA 

11 
§ 

' 

/ 

3 

. 

1 

% 

, 

y 

\ 

,.. 

>,_ 

7.3 
OA 

i 

i 

/ 

/ 

^~ 

\ 

"_ 

, 

^ 

c 

\ 

IA 

LY 

\ 

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\ 

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**^ 

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\ 

7 

X 

•\ 

V 

^ 

.—  - 

/ 

The  effect  of  alcohol  on  nitrogen  elimination.  The  wave-line  represents  the  nitrogen  excreted.  It 
rises  rapidly  in  the  second  period  when  the  fat  of  the  food  was  reduced  to  one  half,  but  soon  falls  in 
the  third  period  where  alcohol  was  substituted.  100  g.  of  alcohol  is  chemically  equivalent  to  78  g. 
of  fat.  (After  NEUMANN.  ) 

the  food.  The  next  ten  days  a  quantity  of  alcohol  chemically  equivalent 
to  the  fat  deficit  was  taken  and  the  nitrogen  elimination  slowly  fell  to 
the  normal  (equilibrium).  In  the  first  five  days  of  this  period,  however, 
the  nitrogen  remained  high,  showing  that  alcohol  did  not  at  first  replace 
the  fats  completely.  In  the  fourth  period  of  six  days,  the  same 
amount  of  fat  was  given  as  at  first,  while  the  alcohol  was  continued, 
and  the  nitrogen  fell  much  below  the  amount  ingested  ;  L  e.,  the  alcohol 
again  led  to  a  saving  of  the  proteids.  Next,  both  alcohol  and  fat 
were  omitted  for  four  days  and  the  proteid  tissues  were  again  drawn 
upon.  Finally  the  original  diet  was  resumed  and  the  nitrogenous 
equilibrium  was  at  once  restored.  From  this  experiment  Neumann 
drew  the  conclusion  that  alcohol  can  replace  a  chemically  equivalent 
amount  of  fat  in  the  dietary,  for  otherwise  the  nitrogen  would  not 
have  returned  to  the  normal  toward  the  end  of  the  third  period  ;  and 
alcohol  given  along  with  a  sufficient  dietary  leads  to  a  further  economy  of 
the  proteids  just  as  additional  fat  would  ;  otherwise  the  nitrogen  would 
not  have  fallen  below  the  point  of  equilibrium  in  the  fourth  period. 
Certain  objections  which  were  made  to  this  experiment  by  Rosemann 
have  been  refuted  by  his  own  work  and  by  Neumann's,  so  that  both 
investigators  are  now  in  accord. 

The  final  result  of  all  these  investigations  is  that  alcohol  can  take 
the  place  of  some  of  the  fat  in  the  food,  and  leads  to  the  same  economy 
of  proteid  as  the  ordinary  non-nitrogenous  constituents  of  the  dietary. 
The  first  three  or  four  days  during  which  alcohol  is  substituted  for  fat 
it  has  little  or  no  tendency  to  economize  the  proteids,  but  this  is  true 
of  other  forms  of  food  also;  any  sudden  change  in  the  non-nitrogenous 


142  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

food  leading  to  a  temporary  increase  in  the  nitrogen  excreted,  which 
persists  until  the  tissues  have  become  accustomed  to  the  new  dietary. 

Metabolism.  —  It  was  formerly  supposed  that  alcohol  economized  the 
body  tissues  in  some  ill-defined  way,  by  means  of  a  direct  action  on 
the  protoplasm  of  the  cells  ;  as  it  was  expressed,  alcohol  lessened  the 
combustion  of  the  tissues.  There  is  no  reason  to  suppose  that  alcohol 
in  ordinary  quantities  has  any  action  on  the  tissues  save  as  a  food,  for, 
as  has  been  mentioned,  the  oxidation  of  the  tissues  as  measured  by  the 
oxygen  absorbed  and  the  carbonic  acid  exhaled  is  only  affected  as  it  is 
by  any  other  food.  When  very  large  quantities  of  alcohol  are  taken, 
and  depression  and  sleep  follow,  the  combustion  of  the  body  is  reduced, 
not  through  any  action  on  the  protoplasm  generally,  but  through  the 
muscular  movements  being  lessened.  In  the  same  way,  during  the  ex- 
citement stage,  the  carbonic  acid  exhaled  is  doubtless  much  increased, 
because  more  energy  and  -more  of  the  body  tissues  is  used  up  in  the 
violent  movements.  Of  course,  the  oxidation  of  alcohol  by  the  tissues 
saves  fat  from  combustion,  and  it  is  possible  that  some  bodies  which 
would  normally  be  oxidized  in  the  organism  may  pass  through  it  un- 
changed in  the  same  way ;  thus  it  is  stated  that  less  benzol  is  oxidized 
in  animals  under  the  influence  of  alcohol  than  in  unpoisoned  ones. 
The  influence  of  alcohol  on  the  uric  acid  excretion  seems  to  vary  with 
the  individual,  for  while  no  definite  change  has  been  observed  in  some 
cases,  even  when  large  quantities  of  alcohol  were  taken,  Beebe  found 
a  distinct  increase  in  the  quantity  excreted  under  moderate  doses.  He 
ascribes  this  result  to  alcohol  disturbing  the  functions  of  the  liver,  and 
further  evidence  of  this  action  has  been  found  by  Paton  and  Eason  in 
the  lower  proportion  of  urea  to  the  total  nitrogen  of  the  urine. 

The  Temperature  of  the  body  falls  somewhat  after  the  administration 
of  alcohol,  but  this  is  not  due  to  any  diminution  in  the  oxidation  and 
in  the  heat  formed,  but  to  the  greater  output  of  heat  from  the  dilation 
of  the  skin  vessels.  The  fall  in  temperature  is  comparatively  slight, 
seldom  being  more  than  J-l°  C.,  but  it  would  seem  that  exposure  to 
cold  causes  a  greater  fall  in  the  temperature  after  alcohol  than  in  nor- 
mal conditions ;  this  is  perhaps  due  to  the  temperature-regulating 
mechanism  being  rendered  less  sensitive  by  alcohol. 

The  fall  in  temperature  produced  by  alcohol  is  generally  accompa- 
nied by  a  feeling  of  heat,  and  a  thermometer  applied  to  the  skin  may 
actually  show  a  rise  of  several  degrees,  because  more  warm  blood  flows 
through  the  dilated  vessels.  If  much  excitement  and  movement  follow 
the  ingestion  of  alcohol,  no  fall  in  the  temperature  may  result,  the  in- 
creased heat  formed  during  the  movement  compensating  for  the  increased 
output,  and  in  some  cases  a  rise  of  temperature  occurs  from  the  same 
cause.  Very  large  quantities  of  alcohol  may  lead  to  a  fall  in  temper- 
ature of  3-5°  C.,  owing  to  the  lessened  movements  during  uncon- 
sciousness. 

The  alcohol  which  escapes  combustion  in  the  tissues  is  excreted  by 
the  kidneys  and  perhaps  by  the  lungs.  Traces  are  sometimes  found 


ALCOHOL.  143 

in  the  sweat  and  milk,  but  there  is  no  foundation  for  the  legend  that 
children  may  be  intoxicated,  or  acquire  a  taste  for  strong  drink  from 
the  alcohol  absorbed  in  the  milk  of  a  drunken  mother  or  wet-nurse. 
The  amount  and  quality  of  the  milk  are  unaffected  by  the  adminis- 
tration of  alcohol  (Rosemann).  Brauer  states  that  alcohol  is  elimi- 
nated in  some  quantity  in  the  bile  and  is  then  reabsorbed  in  the  intes- 
tine. This  is  more  marked  in  the  case  of  amyl  alcohol  than  in  that 
of  ethyl  alcohol,  and  the  appearance  of  alcohol  in  the  bile  is  accom- 
panied by  albumin,  epithelial,  cells  and  casts  of  the  finer  bile  ducts. 

Although  alcohol  seems  to  increase  the  urine  to  some  extent,  it  can- 
not be  said  to  be  a  powerful  diuretic  in  itself,  and  it  is  quite  unknown 
whether  it  acts  on  the  kidney  directly  or  not.  Some  of  the  spirituous 
liquors  such  as  gin,  produce  a  profuse  secretion  of  urine,  but  this  is 
due  to  their  other  constituents,  and  not  to  the  alcohol. 

Alcohol  is  generally  credited  with  aphrodisiac  powers,  that  is,  with 
increasing  sexual  desire,  although  no  less  an  authority  than  Shake- 
speare states  that  it  prevents  the  consummation  of  sexual  intercourse. 
The  unquestionable  tendency  toward  sexual  excess  observed  in  intoxi- 
cation is  due,  not  to  any  effects  on  the  generative  organs,  but  to  the 
loss  of  self-control  from  the  cerebral  action  of  the  poison. 

Alcohol  possesses  only  a  weak  antiseptic  action,  for  while  the 
growth  of  some  bacteria  is  delayed  somewhat  in  a  1  :  1000  solution, 
many  grow  abundantly  in  4  per  cent,  alcohol,  and  some  in  even 
stronger  solutions.  Its  disinfectant  action  has  been  the  subject  of  a 
number  of  researches  recently  and  has  been  found  to  vary  with  the 
conditions.  Dry  bacteria  may  be  exposed  to  absolute  alcohol  for 
twenty-four  hours  without  losing  their  vitality,  while  60-70  per  cent, 
alcohol  is  fatal  to  them,  and  also  to  moist  organisms.  The  explana- 
tion of  this  curious  observation  seems  to  be  that  alcohol  fails  to  pene- 
trate microbes  unless  in  the  presence  of  water.  In  less  than  40  per 
cent,  the  action  is  very  slow,  so  that  the  limits  of  alcohol  as  a  disin- 
fectant may  be  placed  at  50—70  per  cent.  ;  in  this  strength  it  is 
equivalent  to  about  3  per  cent,  carbolic  acid,  provided  that  it  does  not 
cause  large  precipitates  of  proteid.  Many  bodies  which  are  antiseptic 
when  dissolved  in  water  have  comparatively  little  effect  when  dis- 
solved in  alcohol.  (Compare  p.  48.) 

It  has  long  been  recognized  clinically  that  persons  addicted  to  the  use 
of  alcohol  show  less  resistance  in  acute  disease  and  in  operations  accom- 
panied by  shock  than  more  temperate  individuals,  and  in  very  intem- 
perate cases,  the  prognosis  must  be  guarded  in  an  attack  which  would 
ordinarily  be  accompanied  with  little  danger.  This  has  been  confirmed 
by  a  number  of  experiments  on  animals  which  were  subjected  to  treat- 
ment with  alcohol  and  then  inoculated  with  pathogenic  germs 
(Laitinen).  The  results  have  invariably  shown  a  greater  susceptibility 
to  infection  and  a  greater  mortality  than  in  control  animals  which  had 
received  no  alcohol.  A  similar  effect  was  observed  when  toxines  were 
injected  instead  of  bacteria,  and  great  difficulty  was  encountered  in 


144  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

rendering  animals  immune  to  the  diphtheria  toxin  if  they  had  pre- 
viously been  treated  with  alcohol.  Various  explanations  of  this 
reduced  resistance  have  been  given,  Rubin  ascribing  it  to  paucity  or 
inactivity  of  the  leucocytes,  while  Abbott  and  Bergey  found  a  reduc- 
tion in  the  hemolytic  complement,  which  suggests  that  the  suscepti- 
bility to  infection  may  be  due  to  the  failure  to  form  the  specific  com- 
plement to  the  bacterial  toxin.  It  is  often  stated  that  alcohol  given 
in  the  treatment  of  infectious  diseases  must  have  a  similar  deleterious 
effect  on  the  resistance  of  the  tissues,  but  this  has  not  been  shown  to 
be  the  case,  and  some  observers  (Hare,  Friedberger)  indicate  that  it 
favors  the  defence  of  the  organism. 

Repeated  doses  of  alcohol  produce  tolerance,  which,  although  not  so 
great  as  that  acquired  for  morphine  and  nicotine,  involves  the  pre- 
scription of  double  or  triple  doses,  in  persons  addicted  to  drinking. 
The  close  relationship  between  the  narcotics  of  the  fatty  series  is 
indicated  by  the  fact  that  much  more  chloroform  or  ether  than  usual 
is  required  to  anaesthetize  persons  in  whom  a  tolerance  for  alcohol  has 
been  established. 

Methyl  alcohol,  or  wood  alcohol,  has  assumed  great  importance  lately  from 
a  large  number  of  cases  of  poisoning  having  occurred  from  its  being  substituted 
for  ethyl  alcohol  as  an  intoxicant,  or  in  some  patent  remedies.  In  animal 
experiments  it  is  found  that  given  in  single  doses  it  is  slightly  less  poisonous 
than  ethyl  alcohol,  the  action  coming  on  somewhat  more  slowly,  but  lasting  a 
longer  time;  the  symptoms  of  gastric  irritation  are  generally  more  marked  than 
those  induced  by  ethyl  alcohol,  and  very  often  some  convulsive  movements  are 
observed  (Hunt).  When  the  administration  is  repeated,  methyl  alcohol  is  found 
much  more  poisonous  than  ethyl,  and  this  may  probably  be  ascribed  to  the 
more  prolonged  action  of  the  former.  Pohl  has  pointed  out  that  while  ethyl 
alcohol  undergoes  complete  combustion  in  the  tissues,  methyl  alcohol  is  oxidized 
to  formic  acid  and  possibly  formic  aldehyde,  both  of  which  are  much  more 
poisonous  than  the  original  alcohol.  It  seems  a  fair  inference  that  the  pro- 
longed action  and  the  consequent  greater  toxicity  of  the  lower  alcohol  may  be 
due  to  these  products. 

In  man  the  symptoms  of  wood  alcohol  poisoning  differ  from  those  of  ordinary 
spirits  in  the  marked  muscular  weakness  and  defective  cardiac  action,  which  are 
followed  by  nausea,  vomiting,  coma,  or  delirium  of  a  much  more  intense  and 
persistent  character  than  those  seen  in  intoxication  with  ethyl  alcohol.  In  a 
considerable  number  of  cases  death  has  followed  from  a  single  dose  smaller  than 
would  have  been  fatal  had  ethyl  alcohol  been  swallowed,  and  in  some  cases  total 
and  permanent  blindness  has  followed  or  accompanied  recovery.  This  condi- 
tion is  more  often  the  result  of  repeated  ingestion  of  the  alcohol,  however,  and 
is  due  to  optic  neuritis  and  subsequent  complete  optic  atrophy.  The  large 
number  of  cases  of  blindness  or  fatal  intoxication  collected  by  Buller  and 
Wood  demonstrate  clearly  the  danger  incurred  in  the  use  of  this  poison  inter- 
nally or  even  externally.  Optic  atrophy  has  been  induced  in  animals  repeat- 
edly by  the  administration  of  wood  alcohol,  and  is  certainly  much  less  liable  to 
occur  from  ethyl  alcohol. 

The  other  alcohols  are  mainly  of  interest  as  impurities  of  the  preparations 
of  ethyl  alcohol.  They  all  resemble  it  in  their  general  effects,  but  differ  from 
it  in  toxicity;  propyl  alcohol  is  more  powerful  than  ethyl,  butyl  than  propyl, 
and  amyl  than  any  of  them.  Amyl  alcohol,  or  fusel  oil,  is  present  in  small 
quantity  in  most  forms  of  spirits,  especially  when  these  are  freshly  distilled  or 
' '  raw. ' '  It  resembles  ethylic  alcohol  in  general,  but  is  more  irritant  locally, 


ALCOHOL.  145 

and  is  believed  by  some  authorities  to  have  more  deleterious  effects  in  chronic 
poisoning  than  pure  ethylic  alcohol.  This  is  not  based  on  any  very  satisfactory 
evidence,  however,  and  all  the  characteristic  symptoms  of  chronic  alcoholism 
have  been  produced  in  animals  by  pure  ethyl  alcohol.  Furfurol  is  also  present 
in  many  forms  of  spirits,  but  in  such  small  quantities  that  it  does  not  play  any 
role  in  the  symptoms  induced  by  them. 

PREPARATIONS. 

Alcohol  (U.  S.  P.)  contains  92$  of  alcohol  (C2H.HO)  by  weight. 

Alcohol  Absolut um  (U.  S.  P.,  B.  P.),  absolute  alcohol,  contains  not  more  than 
1  %  >  by  weight,  of  water. 

Alcohol  Dilutum  (U.  S.  P.)  contains  about  41$,  by  weight,  of  alcohol. 

Spiritus  Rectificatus  (B.  P.),  rectified  spirit,  contains  90  parts  of  pure  alco- 
hol, by  volume,  and  10  parts  of  water  (85.65$,  by  weight,  of  alcohol). 
There  are  four  official  dilutions  in  the  B.  P.,  containing  70,  60,  45  and  20 
per  cent,  of  alcohol  by  volume  respectively. 

SPIRITUS  FRUMENTI  (\J.  S.  P.),  whiskey,  contains  44-50$  of  alcohol  by 
weight,  and  is  obtained  by  distillation  of  an  extract  of  fermented  grain. 

SPIRITUS  VINI  GALLICI  (U.  S.  P.,  B.  P.),  brandy,  contains  39-47$  of  alco- 
hol by  weight,  and  is  obtained  by  the  distillation  of  fermented  grape  juice. 

Mistura  Spiritus  Vini  Gallici  (B.  P.),  a  mixture  of  brandy,  cinnamon  water, 
sugar  and  yolk  of  egg  (about  17  per  cent,  alcohol).  Dose,  1-2  fl.  oz. 

Non-pharmacopceial  spirits,  which  are  used  occasionally  in  medicine,  are 
gin  and  rum. 

These  Spirits  all  contain,  roughly  speaking,  about  one  half  as  much  alco- 
hol as  the  three  concentrated  alcohols  of  the  U.  S.  P.  or  the  rectified  spirits 
of  the  B.  P.  They  contain,  in  addition  to  the  ethyl  alcohol  proper,  numbers 
of  other  volatile  substances,  some  of  which  are  alcohols  of  the  same  series 
as  ordinary  alcohols  (butylic,  amylic,  etc.),  while  others  are  of  entirely 
unknown  constitution — the  cenanthic  ethers.  Brandy  and  whiskey  act  very 
much  in  the  same  way  as  pure  alcohol,  but  are  more  powerful  than  would 
be  expected  from  the  percentage  of  alcohol  alone.  When  freshly  distilled 
they  are  much  more  irritant  than  when  kept  for  some  years.  Numerous 
other  preparations  containing  large  quantities  of  alcohol,  such  as  the  spirits 
of  the  volatile  oils,  might  also  be  included  in  this  group,  but  they  are  not 
used,  as  a  general  rule,  for  the  same  purposes  as  the  alcoholic  preparations 
proper,  and  their  effects  are  in  part  due  to  the  volatile  oils  contained. 
Some  of  them  have,  however,  been  employed  as  intoxicants  instead  of 
brandy  or  whiskey,  and  Eau  de  Cologne  and  other  essences  have  gained  a 
certain  notoriety  as  a  means  of  secret  drinking  among  women.  The  liqueurs 
are  too  numerous  to  mention,  and  their  composition  is  extremely  diverse. 
Many  of  them  contain  considerable  quantities  of  sugar,  and  the  combination 
of  alcohol  and  sugar  would  seem  peculiarly  deleterious  to  the  gastric  mucous 
membrane.  Others,  such  as  cherry  water  (Kirschwasser),  contain  hydrocy- 
anic acid,  and  the  others  various  bodies  of  the  volatile  oil  series.  None  of 
them  seem  to  have  any  properties  which  would  recommend  their  use  in 
therapeutics. 

The  Wines  and  Beers  are  much  weaker  preparations  of  alcohol.  The 
U.  S.  P.  recognizes  two  forms  of  wine,  YINUM  ALBUM  (white  wine)  and 
VINUM  RUBRUM  (red  wine,  claret).  These  both  contain  7-12$  of  alcohol 
by  weight,  along  with  1.5-3$  of  solid  matter  in  the  white  wine  and  1.6- 
3.5$  in  the  red.  The  YINUM  XERICUM  (sherry)  of  the  B.  P.  contains  not 
less  than  16$  of  alcohol  by  volume,  while  the  VINUM  AURANTII  (B.  P.),  or 
orange  wine,  contains  10-12$  by  volume.  In  addition,  the  wines  contain 
the  same  volatile  constituents  as  brandy,  although  in  smaller  amounts. 
Other  wines  are  prescribed  in  medicine,  some  of  which,  such  as  port 
10 


146  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

(15-20^),  contain  larger,  and  others  smaller  quantities  of  alcohol  (hock  and 
champagne  8-13%).  The  red  wines  contain  a  form  of  tannic  acid  derived 
from  the  skin  of  the  grapes,  and  both  red  and  white  often  contain  consider- 
able quantities  of  acids,  chiefly  tartaric  acid.  The  amount  of  sugar  varies 
with  the  different  wines,  and  in  fact  in  wine  from  the  same  locality  but  of 
different  seasons.  These  constituents  may  lend  to  the  wines  a  local  dele- 
terious action  on  the  stomach,  more  especially  when  they  are  taken  habitu- 
ally. Champagne  and  the  other  sparkling  wines  contain  large  quantities  of 
carbonic  acid,  which  acts  as  a  stimulant  to  the  gastric  mucous  membranes. 
Champagne  is  considered  one  of  the  most  l '  stimulant ' '  of  alcoholic  prepa- 
rations, although  it  contains  a  very  low  percentage  of  alcohol  compared  with 
spirits,  a  fact  which  is  of  some  significance  in  the  explanation  of  the  "stim- 
ulant" effects  of  alcohol. 

The  beers  are  not  pharmacopceial,  and  are  less  frequently  advised  than 
the  other  preparations.  They  generally  contain  a  comparatively  small  per- 
centage of  alcohol  (4-10%),  along  with  a  large  amount  of  solids.  These 
solids  consist  mainly  of  dextrin,  sugar  and  other  starch  products,  which  retard 
the  absorption  of  the  fluid,  but  are  of  considerable  value  as  foods.  The  hops 
added  in  the  preparation  have  probably  no  action  save  as  bitter  stomachics. 
The  alcohol  of  beer  is  comparatively  slowly  absorbed  owing  to  the  colloid 
constituents,  and  this  allows  time  for  fermentation  changes  in  the  sugars  and 
dextrins,  which  may  perhaps  account  for  the  discomfort  produced  by  malt 
liquors  in  persons  of  feeble  digestion.  When  beers  and  porter  do  not  de- 
range the  digestion,  they  are  the  most  nutritive  of  all  the  alcoholic  prep- 
arations, owing  to  the  large  amount  of  carbohydrates  they  contain. 

Therapeutic  Uses. — Alcohol  is  used  externally  in  very  dilute  solution 
as  a  cooling  application  to  the  skin,  and  in  threatening  bedsores,  in 
which  it  is  often  applied  as  brandy,  whiskey,  or  dilute  alcohol  in  order 
to  harden  the  epidermis.  It  has  been  employed  as  an  antiseptic  and 
mild  irritant  to  broken  surfaces,  and  if  applied  to  the  skin  in  concen- 
trated form,  and  especially  if  kept  from  evaporation,  acts  as  a  rubefa- 
cient  and  irritant.  In  the  form  of  diluted  claret  it  is  not  infrequently 
used  as  an  astringent  gargle. 

The  indications  for  the  internal  use  of  alcohol  are  ill  defined,  and 
cases  which  one  physician  would  treat  with  alcohol,  often  seem  to  pro- 
gress as  favorably  without  it  in  the  hands  of  another.  It  is  not  suffi- 
ciently recognized  that  this  drug  possesses  several  different  qualities,  as 
local  irritant,  narcotic  and  food  and  that  while  one  property  considered 
alone  might  render  it  unadvisable  in  a  given  condition,  the  deleterious 
effect  induced  in  this  direction  may  be  more  than  counterbalanced  by 
its  valuable  results  in  other  directions.  At  the  same  time  it  would  be 
preferable  in  most  cases  to  substitute  for  this  conjunction  of  good  and 
bad  properties  other  drugs  with  a  less  extended  sphere  of  action. 

One  series  of  symptoms  which  is  often  treated  with  wines  is  of  gas- 
tric origin,  and  is  manifested  in  want  of  appetite  and  enfeeblement  of 
the  digestion ;  in  some  of  these  cases  the  alcoholic  preparations  seem  to 
be  beneficial,  while  in  others  they  appear  to  be  positively  harmful.  This 
may  be  explained  by  the  effect  of  alcohol  on  secretion  and  absorption, 
only  those  cases  in  which  secretion  is  deficient  being  benefited,  but  the 
tastes  of  the  patient  are  also  an  important  factor  ;  if  he  enjoys  the  taste 
and  odor  of  wine,  its  administration  may  promote  his  appetite,  while, 


ALCOHOL.  147 

on  the  other  hand,  if  he  has  a  distaste  for  wine,  it  will  prove  harmful. 
There  is  no  question  that  the  functions  of  the  stomach  are  increased  by 
pleasing,  and  retarded  by  unpleasant  tastes  and  odors.  In  these  cases 
"dry"  wines  are  to  be  preferred,  as  the  sugar  of  the  sweet  wines  may 
irritate  the  stomach  ;  champagne  may  be  used,  and  the  wine  ought  to 
be  given  immediately  before  or  during  a  meal. 

Cases  of  hemorrhage,  shock,  and  other  forms  of  severe  and  sudden 
depression  of  the  heart  and  central  nervous  system  are  very  frequently 
treated  by  the  administration  of  strong  alcoholic  preparations,  such  as 
brandy  and  whiskey,  this  treatment  being  based  upon  the  belief  that 
alcohol  is  a  cardiac  and  respiratory  stimulant,  the  grounds  for  which 
have  already  been  examined.  It  is  extremely  difficult  to  estimate  the 
value  of  a  remedy  in  these  conditions,  and  it  is  possible  that  the  irri- 
tant action  of  alcohol  in  the  stomach  may  increase  the  activity  of  the 
medullary  centres  refiexly,  or  that  by  its  narcotic  action  it  may  lessen 
the  anxiety  and  pain  of  the  patient.  On  the  other  hand,  in  cases  of 
inhibitory  slowing  of  the  heart  it  may  aid  by  lessening  the  activity  of 
the  vagus  centre  in  the  medulla.  But  the  beneficial  effects  of  alcohol 
in  these  cases  has  been  much  questioned  in  recent  years  and  the  belief 
that  it  is  of  little  value  is  certainly  more  widely  held  at  present  than 
at  any  previous  time;  in  experimental  shock  in  animals,  Crile  found 
that  alcohol  generally  increased  the  danger  when  given  in  average  doses, 
and  that  smaller  doses  had  no  beneficial  effects,  but  it  is  quite  possible 
that  in  man  different  results  may  be  obtained  from  alcohol  acting  as  a 
narcotic  and  removing  nervous  symptoms  which  would  not  arise  in  the 
lower  animals. 

In  sudden  chill  with  a  tendency  to  fever,  alcohol  is  often  of  great 
benefit,  especially  when  taken  in  the  form  of  brandy  or  whiskey 
diluted  with  hot  water.  Its  efficacy  here  would  seem  due  to  the  relief 
of  the  congestion  of  the  internal  organs  by  the  return  of  the  blood  to 
the  skin. 

In  many  cases  of  acute  inflammatory  disease,  the  prescription  of  alco- 
hol seems  to  be  attended  with  benefit,  while  in  others  it  seems  rather  to 
increase  the  severity  of  the  symptoms.  No  special  indications  can  be 
given  for  alcohol  in  these  cases,  and  the  physician  must  be  guided 
by  its  effects.  An  old  rule  advised  that  if  the  pulse  becomes  slower, 
the  temperature  falls,  the  respiration  is  deeper,  the  nervous  symptoms 
are  ameliorated  and  the  skin  becomes  moister  after  the  administration 
of  alcohol,  the  treatment  ought  to  be  continued ;  but  this  is  merely 
equivalent  to  advising  the  continued  administration  of  alcohol  when  it 
is  found  to  improve  the  symptoms.  The  effect  of  alcohol  in  these 
cases  is  often  said  to  be  a  stimulant  one  on  the  heart  and  central  nerv- 
ous system,  but  it  would  rather  seem  to  allay  the  irritability  of  the 
nervous  centres,  and  thus  reduce  the  delirium  and  slow  the  heart  and 
respiration  by  lessening  the  muscular  movement.  Moreover,  the  tissue 
waste  is  much  increased  in  fever,  and  at  the  same  time  the  food  absorp- 
tion is  less  than  normally,  so  that  many  of  the  symptoms  may  be  due  to 


148  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

starvation  of  the  tissues.  The  food- value  of  alcohol  is  unchanged  by  the 
presence  of  fever  (Ott)  ;  it  demands  less  energy  from  the  digestive  organs 
than  fats  and  starchy  foods,  and  has  a  higher  value  as  a  producer 
of  energy  than  sugar.  It  cannot  supply  the  place  of  the  nitrogenous 
foods,  but  given  along  with  them,  may  lead  to  a  greater  economy  of 
the  tissues.  It  is  to  be  remarked  that  according  to  Neumann  alcohol 
fails  to  have  this  effect,  at  any  rate  in  normal  individuals,  until  it  has 
been  given  for  several  days,  so  that  if  it  is  to  be  used  as  a  food,  it 
ought  to  be  given  early  in  the  disease.  Strong  wines  or  diluted  spirits 
are  generally  employed  here  and  ought  to  be  given  in  small  quantities 
frequently.  Alcohol  was  formerly  advocated  especially  in  septic  con- 
ditions, and  here  it  may  be  of  value  on  the  same  grounds  as  in  acute 
fevers,  although  it  does  not  seem  to  have  any  specific  action  in  septic 
disease,  as  was  once  believed.  A  protest  has  recently  been  raised 
against  the  use  of  alcohol  in  these  cases,  on  the  ground  that  animals 
subjected  to  alcohol  succumb  more  readily  to  infection  than  controls 
which  have  received  no  treatment,  and  this  has  been  shown  to  be  true 
even  when  the  dose  of  alcohol  was  proportionate  to  that  often  advised 
in  the  treatment  of  these  cases  in  man  (Laitinen).  This  is  undoubtedly 
an  objection  of  great  weight,  but  it  must  not  be  forgotten  that  though 
alcohol  may  be  deleterious  in  this  way,  this  may  be  more  than  com- 
pensated for  by  its  value  as  a  food,  and  by  its  narcotic  effects  allaying 
the  nervous  irritability  and  promoting  sleep  ;  this  narcotic  action  may 
very  well  be  conceived  to  be  of  benefit  to  man,  while  actually  preju- 
dicial to  animals. 

In  some  chronic  forms  of  nervous  disease  alcohol  may  also  be  of 
value,  although  its  administration  must  always  be  guarded,  owing  to 
the  tendency  to  the  formation  of  the  alcohol  habit.  Thus,  in  some 
forms  of  melancholia  and  of  neuralgia  it  gives  relief,  partly  probably 
through  its  depressant  action  on  the  brain  and  partly  from  its  local 
action  on  the  digestion.  Some  authorities  recommend  the  use  of  alco- 
hol in  small  quantities  in  cases  of  distress  of  mind  from  any  cause, 
such  as  grief,  business  anxiety  or  depression,  and  undoubtedly  alcohol 
improves  these  conditions  by  its  narcotic  action  on  the  brain.  But 
the  danger  of  the  alcohol  habit  is  so  great,  that  many  physicians  refuse 
to  take  the  responsibility  of  prescribing  the  drug  in  these  cases. 

In  chronic  conditions  of  cachexia  and  loss  of  flesh  in  general,  and 
during  convalescence,  alcoholic  preparations  are  often  advised  simply 
as  foods,  and  in  these  cases  the  ales,  beers  and  porters  are  generally  to 
be  preferred  to  the  others,  provided  always  that  the  stomach  is  not 
irritated  by  them,  as  they  contain  other  food-stuffs  of  value  in  addition 
to  the  alcohol. 

In  poisonous  snake  bite,  alcohol  is  generally  administered  in  enor- 
mous quantities,  either  as  whiskey  or  brandy,  but  it  seems  open  to 
question  whether  it  is  really  of  value  in  these  cases,  and  its  action  on 
the  normal  tissues  certainly  gives  no  indication  for  its  use  here. 

Alcohol  is  of  value  as  a  mild  hypnotic,  a  comparatively  small  quan- 


ALCOHOL.  149 

tity  taken  before  retiring  being  often  sufficient  to  secure  quiet  and 
refreshing  sleep.  Beer  or  spirits  and  water  is  generally  used  for  this 
purpose. 

Brandy  has  a  certain  reputation  in  the  treatment  of  the  milder 
forms  of  diarrhrea,  while  the  other  spirits  have  no  effect  in  this  condi- 
tion. The  means  by  which  this  effect  is  accomplished  are  unknown. 

In  the  prescription  of  alcohol,  the  ordinary  spirits,  brandy  or  whis- 
key, are  very  much  more  frequently  advised  than  the  purer  prepara- 
tions, as  the  latter  are  more  apt  to  pall  upon  the  taste  of  the  patient. 
Both  of  these  spirits  ought  to  be  diluted  with  at  least  an  equal  quan- 
tity of  water.  The  wines  are  more  used  in  chronic  conditions,  although 
diluted  spirits  may  be  advised  here  also.  Beers  are  employed  only  in 
debility  unaccompanied  by  gastric  symptoms. 

Alcohol  can  be  given  to  children  in  relatively  larger  quantities  than 
to  adults,  and  again  in  old  age  no  such  reduction  in  the  dose  is  required 
as  in  the  case  of  many  other  drugs.  Where  a  tolerance  for  alcohol  has 
been  established,  the  dose  has  often  to  be  more  than  doubled  in  order 
to  have  any  effect,  and  in  acute  febrile  conditions  very  large  quantities 
of  alcohol  are  often  given  without  intoxication,  though  it  seems  ques- 
tionable whether  an  equally  beneficial  result  could  not  be  attained  with 
much  smaller  doses.  In  gastric  irritation,  most  preparations  of  alco- 
hol are  contraindicated,  but  champagne  is  often  of  benefit  in  checking 
vomiting,  especially  that  of  pregnancy  and  of  seasickness,  this  effect 
being  due  to  the  carbonic  acid,  not  to  the  alcohol.  In  nephritis  and 
other  inflammatory  conditions  of  the  genito-urinary  tract,  alcohol  is 
generally  avoided  on  account  of  its  supposed  effects  on  the  epithe- 
lium. 

In  regard  to  the  habitual  use  of  alcohol  by  healthy  persons  all 
authorities  agree  that  it  is  a  luxury,  that  it  is  entirely  unnecessary  for 
the  growth  and  maintenance  of  the  body,  but  that  taken  in  moderate 
quantities  it  is  harmless,  except  from  the  danger  that  this  may  lead  to 
the  habit  being  formed.  The  habitual  indulgence  in  alcohol  to  excess 
is  more  easily  intelligible  than  some  other  chronic  intoxications,  for, 
unlike  nicotine,  alcohol  is  taken  not  only  for  its  local  effects  on  the 
organs  of  taste  and  on  the  mucous  membranes  of  the  mouth  and 
stomach,  but  also  for  its  action  on  the  brain  in  numbing  the  con- 
sciousness of  unhappiness,  and  this  weakening  of  the  higher  sensibilities 
by  drink  is  generally  the  object  sought  by  the  drunkard.  He  finds 
that  under  alcohol  his  habitual  depression  disappears,  and  he  loses  the 
sense  of  degradation  and  remorse  which  possesses  him  when  sober. 
The  depression  returns  in  exaggerated  form  after  the  effects  of  the 
drug  have  passed  off,  but  it  can  be  removed  again  by  the  same  means, 
and  in  this  way  the  habit  is  formed,  each  successive  dose  being 
rendered  necessary  by  the  depression  produced  by  its  predecessor. 
This  descent  into  chronic  drunkenness  is  facilitated  by  the  lessening 
of  the  self-control  owing  to  the  action  of  alcohol  on  the  brain.  The 
victim  may  form  the  best  of  resolutions,  but  his  impaired  will  power 
and  self-control  are  unable  to  carry  them  out. 


150  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

The  symptoms  of  Chronic  Alcoholism  are  unfortunately  common,  but 
may  be  treated  better  in  detail  in  connection  with  various  forms  of  dis- 
ease, with  which  they  are  associated  more  closely  than  with  the  effects 
produced  by  the  medicinal  use  of  the  drug.  The  earliest  symptoms 
are  generally  observed  in  the  stomach,  throat  and  larynx,  and  consist 
of  a  chronic  catarrh,  which  is  often  accompanied  by  skin  affections, 
such  as  injection  of  the  cutaneous  vessels  (especially  of  those  of  the 
face),  acne  or  pustular  eruptions.  The  irritation  spreads  from  the 
stomach  to  the  liver  and  kidney,  and  produces  fatty  degeneration  and 
necrosis  of  the  cells,  followed  by  increased  growth  of  the  interstitial 
connective  tissue,  and  cirrhosis  of  these  organs.  The  fatty  degenera- 
tion is  also  found  in  the  arterial  walls  throughout  the  body,  and  causes 
atheroma  and  arterio-sclerosis,  which  may  lead  to  small  aneurysmal 
dilatations,  ecchymoses,  or  apoplexy.  The  heart  undergoes  more  or 
less  fatty  change,  which  is  accompanied  by  dilatation  and  weakness. 
In  the  central  nervous  system,  the  nutrition  is  imperfect  owing  to  the 
vascular  changes,  but  in  addition  to  this,  alcohol  has  a  special  action 
on  the  neurons,  which  is  betrayed  by  the  disappearance  of  the  chro- 
matin  granules,  and  eventually  by  shrinkage  of  the  whole  cell.  The 
dendrites  show  moniliform  enlargements  along  their  course,  and  in  the 
later  stages  the  finer  dendrites  disappear  entirely.  These  alterations 
in  the  central  nervous  system  lead  to  impairment  of  memory,  self- 
control  and  the  other  higher  mental  processes.  Tremor,  convulsive 
attacks,  hallucinations  and  mania  are  eventually  followed  by  idiocy 
and  paralysis  in  the  worst  forms  of  the  disease.  The  peripheral  nerves 
seem  to  be  acted  on  directly  as  well  as  through  the  changes  in  the 
centres,  for  neuritis  has  been  frequently  observed,  ending  in  local 
paralysis.  A  form  of  amblyopia  commencing  by  atrophy  of  the  retinal 
ganglion  cells  and  later  extending  to  the  fibres  of  the  optic  nerve 
has  recently  received  some  attention ;  it  is  much  more  readily  elicited 
by  methyl  than  by  ethyl  alcohol.  A  characteristic  result  of  chronic 
alcoholism  is  delirium  tremens,  an  acute  attack  of  insanity,  which  is 
liable  to  occur  after  any  shock,  such  as  hemorrhage  or  acute  disease, 
but  which  is  said  to  be  also  produced  by  the  sudden  withdrawal  of 
alcohol,  and  sometimes  occurs  without  any  apparent  immediate  cause. 
It  is  characterized  by  tremor,  perspiration,  sleeplessness,  fear,  ex- 
citement and  hallucinations  of  the  various  senses,  which  differ  from 
many  other  hallucinations  of  insanity  in  consisting  of  the  multiple 
appearance  of  the  same  object.  These  objects  are  often  animals, 
such  as  snakes,  rats,  dogs,  but  the  hallucinations  are  not  confined  to 
those  of  sight,  for  whispering  voices  are  complained  of  not  infre- 
quently. 

The  more  severe  forms  of  chronic  alcoholism  are  confined  almost 
entirely  to  the  drinkers  of  undiluted  spirits.  Beers  and  wines  seldom 
have  any  distinct  action  on  the  brain  in  themselves,  unless  spirits  are 
also  indulged  in.  The  abuse  of  the  weaker  preparations  of  alcohol  is 
always  liable  to  lead  to  that  of  the  stronger,  however,  as  tolerance  is 


ALCOHOL.  151 

established  and  the  former  lose  their  effect.  The  combination  of  spirits 
and  malt  liquors  is  said  to  be  more  liable  to  produce  delirium  tremens 
than  the  abuse  of  either  alone. 

The  disastrous  effects  of  the  abuse  of  alcohol  are  seen  in  the  statistics 
of  the  hospitals,  prisons,  and  asylums,  and  unfortunately  these  show 
an  increase  in  the  number  of  victims  almost  every  year  and  in  nearly 
all  countries,  but  more  especially  in  those  in  which  the  population  is 
addicted  to  spirits.  In  Prussia,  in  1886-1888,  11  per  cent,  of  the 
cases  admitted  to  the  insane  asylums  were  diagnosed  as  directly  due  to 
alcoholic  excess,  while  in  one  of  the  Berlin  asylums  the  enormous  per- 
centage of  47.4  of  the  admissions  were  found  to  be  addicted  to  alcohol. 
In  France,  in  1888,  one  eighth  of  the  cases  of  suicide  were  due  to 
alcoholic  excess.  In  Paris,  72  per  cent,  of  the  convicted  criminals  in 
one  year  were  found  to  be  chronic  alcoholists,  while  the  proportion  in 
Berne  Canton  was  about  40  per  cent.  These  numbers  are  officially 
certified  to  be  correct,  but  give  only  an  imperfect  idea  of  the  deplor- 
able results  of  alcoholic  abuse,  as  only  the  more  extreme  cases  come 
under  the  categories  of  criminals  or  lunatics,  and  the  enormous  num- 
ber of  cases  of  disease  directly  caused  or  aggravated  by  the  lesions 
due  to  alcohol  escapes  recognition.  At  the  same  time,  it  is  beginning 
to  be  appreciated  that  chronic  alcoholism  itself  is  probably  due  to  a 
mental  defect,  so  that  in  a  certain  number  of  these  cases  of  insanity 
and  crime,  the  over-indulgence  in  alcohol  must  probably  be  considered 
a  symptom  and  not  a  cause.  Attempts  have  been  made  of  late  years 
to  demonstrate  that  the  effects  of  alcohol  are  hereditary,  that  the  chil- 
dren of  alcoholists  supply  a  larger  proportion  of  cases  of  insanity  and 
crime  than  those  of  the  rest  of  the  population.  The  belief  is  widely 
entertained  among  biologists,  however,  that  acquired  characters  such 
as  alcoholism  are  not  inherited  directly,  but  can  only  affect  the  nutri- 
tion of  the  offspring.  It  would  seem  more  probable,  then,  that  the 
alcoholic  excesses  of  the  parent  have  no  direct  effect  on  the  offspring, 
except  in  their  nutrition  at  birth,  but  that  the  mental  defect  which 
leads  to  alcoholic  excess  in  the  one  generation  is  inherited  and 
leads  to  crime  or  insanity  in  the  next.  The  deleterious  effect  of  the 
alcoholic  habit  in  the  parent  on  the  nutrition  of  the  offspring  is  a  well- 
established  fact.  It  has  been  shown  experimentally  by  Hodge,  who 
states  that  only  a  small  percentage  of  the  puppies  born  of  parents 
treated  with  alcohol  survive,  and  further  that  they  are  peculiarly  liable 
to  infectious  disease,  such  as  distemper. 

The  treatment  of  acute  alcoholic  intoxication  is  to  evacuate  the  stom- 
ach by  means  of  the  soft  elastic  tube.  The  patient  ought  to  be  put  in 
bed  and  kept  warm,  as  there  is  a  tendency  to  a  marked  fall  in  the 
body  temperature.  In  case  of  great  congestion  of  the  brain,  cold  may 
be  applied  in  the  form  of  ice-bags  to  the  head,  and  some  authorities 
recommend  bleeding.  In  cases  of  extremely  deep  unconsciousness, 
nervous  stimulants,  such  as  caffeine  or  strychnine,  may  be  had  recourse 
to,  and,  as  a  last  resort,  artificial  respiration. 


152  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Chronic  alcoholism  is  to  be  treated  by  the  withdrawal  of  the  poison, 
and  this  is  best  done  gradually,  as  the  immediate  stoppage  may  lead  to 
delirium  tremens.  It  is  often  necessary  to  incarcerate  the  patient  in 
some  retreat.  A  large  number  of  drugs  have  been  advocated  in  these 
cases,  some  of  them  such  as  opium  acting  as  substitutes  for  alcohol, 
others  (capsicum)  replacing  the  local  action  on  the  stomach.  The  use 
of  opium  and  other  narcotics  may  however  lead  to  a  craving  for  these 
which  is  quite  as  serious  as  the  original  condition.  Another  method 
of  treatment,  which  appears  to  be  successful  in  some  cases,  is  the  ad- 
dition of  nauseating  drugs  such  as  ipecacuanha  or  apomorphine  to  the 
alcohol  which  is  supplied  to  the  patient.  The  association  of  nausea 
with  liquor  eventually  becomes  so  strong  that  alcohol  in  any  form 
becomes  distasteful.  The  organic  lesions  must  be  treated  individ- 
ually. 

The  treatment  of  delirium  tremens  generally  consists  in  the  use  of 
chloral  or  opium  to  lessen  the  excitement.  It  is  often  necessary,  or  at 
any  rate  advisable,  in  these  cases  to  allow  small  quantities  of  alcohol, 
as  the  sudden  withdrawal  may  aggravate  the  condition. 

BIBLIOGRAPHY. 

An  admirable  critical  survey  is  given  by  Abel,  Atwater,  Chittenden  and  Welch,  in 
Physiological  Aspects  of  the  Liquor  Problem,  Boston  and  New  York,  1903. 

G.  Rosenfeld.  Der  Einfluss  des  Alkohols  auf  den  Organismus.  Wiesbaden,  1901 
(very  complete  bibliography). 

Binz,  Jaksch.     Verhandl.  des  VII.  Congress  f.  innere  Medicin,  1888,  pp.  70,  86. 

Bunge.     Die  Alkoholfrage,  Leipzig,  1887. 

Jacquet.     Die  Stellungsnahme  des  Arztes  zur  Abstinenzfrage,  Basel,  1896. 

Pohl     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi.,  p.  281. 

Berkeley.     Brain,  xviii.,  p.  473. 

Brandl,  Scanzoni,  Farnsteiner.     Ztschr.  f.  Biol.,  xxix.,  p.  277 ;  xxxiii.,  pp.  462,  475. 

Chittenden  and  Mendel.     Amer.  Jour.,  of  the  Med.  Sciences,  1896,  p.  35. 

Kraepelin.  Ueber  die  Beeinflussung  einfacher  psychischer  Vorgange  durch  einige 
Arzneimittel,  Jena,  1892.  And  in  Kraepelin's  Psych ologische  Arbeiten,  i.-iv.,  passim. 

Jacquet.     Arch,  de  Pharrnacodynamique,  ii.,  p.  107. 

Ndcke.     Deutsch.  Arch.  f.  klin.  Med.,  xxv.,  p.  416.     (Delirium  tremens  ) 

Baer.     Arch.  f.  [Anat.  u.^Phys.,  1898,  p.  283. 

Liepmann.     Arch.  f.  Psychiatrie,  xxvii.,  p.  172. 

Gudden.     Ibid.,  xxviii.,  p.  643. 

Radzikowski.     Pfliiger's  Arch.,  Ixxxiv.,  p.  513. 

Spiro.     Munch,  med.  Woch.,  1901,  p.  1871. 

Boedecker.     Arch.  f.  Psychiatrie,  xxvii.,  p.  810. 

Chittenden,  Mendel  and  Jackson.     Amer.  Journ.  of  Physiol.,  i.,  p.  164. 

Zuntz  and  Magnus-Levy.     Pfliiger's  Arch.,  xlix.,  p.  438;  liii.,  p.  544. 

Deltio.     Centralbl.  f.  Nervenheilkunde  und  Psychiatrie,  1895,  p.  113. 

Brauer.     Ztschr.  f.  Physiol.  Chem.,  xl.,  p.  182. 

Dieballa.     Arch.  f.  exp.  Path.  u.  Pharm,  xxxiv.,  p.  154. 

Weissenfeld.     Pfliiger's  Archiv,  Ixxi.,  p.  60. 

Wendelstadt.     Ibid.,  Ixxvi.,  p.  223. 

Singer.     Arch,  internat.  de  Pharmacodyn.,  vi.,  p.  493. 

Schumberg.     Arch.  f.  [Anat.  u.]  Phys.,  1899,  Suppl.,  p.  289. 

Sche/er.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv.,  p.  24. 

Hellsten.     Skand.  Arch.  f.  Phys.,  xvi.,  p.  139. 

Schnyder.     Pfliiger's  Arch.,  xciii.,  p.  451. 

Rosemann.     Pfliiger's  Arch.,  Ixxvii.,  p.  405;  Ixxxvi.,  p.  307. 

Neumann.     Arch.  f.  Hyg.,  xxxvi.,  p.  1  ;  xli.,  p.  85. 

Atwater  and  Benedict.      U.  S.  Dept.  of  Agriculture  Exper.  Station  Bulletin  No.  69. 

Ott.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvii.,  p.  267. 


ETHER  AND  CHLOROFORM.  153 

Grehant.     Journ.  de  1' Anatomic,  xxxvi.,  p.  143. 

Abbott.  Journ.  of  Exp.  Med.,  L,  p.  447 ;  Univ.  of  Pennsylvania  Med.  Bull.,  Sept., 
1902. 

Laitinen.    Ztschr.  f.  Hygiene,  xxxiv.,  p.  206.     Acta  Societat.  Scient.  Fennic.,  xxix. 

Rubin.    Journ.  of  Infectious  Diseases,  i.,  p.  425. 

Friedberger.     Berlin,  klin.  Woch.,  1904,  p.  242. 

Hare.     Trans.  Assoc.  Amer.  Physicians,  1903,  p.  391. 

Birch-Hirsch/dd.     Arch.  f.  Ophthalraologie,  lii.,  p.  358 ;  liv.,  p.  68. 

Paton  and  Eason.     Jour,  of  Physiol.,  xxvi.,  p.  166. 

Beebe.     Amer.  Journ.,  of  Physiol.,  xii.,  p.  13. 

Harrington.     Boston  Med.  and  Surg.  Journal,  1903  (germicidal  action). 

Weigl.     Arch.  f.  Hygiene,  xliv.,  p.  273  (germicidal  action). 

Wirgin.     Ztschr.  f.  Hygiene,  xl.,  p.  307  ;  xlvi.,  p.  149  (germicidal  action). 

Hunt.     Johns  Hopkins  Hospital  Bulletin,  xiii.,  1902. 

Buller  and  Wood.     Journ.  of  Amer.  Med.  Assoc.,  1904,  II. 

2.    General  Anaesthetics  —  Ether  and  Chloroform. 

The  term  general  anaesthetics  is  employed  to  indicate  substances  used 
to  produce  unconsciousness  sufficiently  complete  to  allow  of  surgical 
operations  being  performed.  In  the  history  of  medicine  there  are 
repeatedly  obscure  allusions  to  substances  used  for  this  purpose,  but  it 
was  not  until  the  end  of  the  first  half  of  the  nineteenth  century  that  the 
era  of  surgical  anesthesia  really  opened.  In  1798,  Davy  advised  the 
use  of  nitrous  oxide  as  an  anaesthetic,  but  no  practical  use  was  made  of 
his  suggestion,  and  Wells  may  be  said  to  have  rediscovered  this  property 
of  the  gas  in  1844,  though  his  efforts  to  introduce  it  into  general  use 
met  with  no  greater  success  than  Davy's.  Long  used  ether  in  1842— 
1843  in  surgical  operations,  but  did  not  give  any  publicity  to  his  dis- 
covery, and  the  honor  of  demonstrating  publicly  the  practical  use  of 
ether  in  surgery  must  be  awarded  to  Jackson  and  Morton  in  1846.  In 
1847,  Simpson  introduced  chloroform  to  the  medical  profession  as  a 
substitute  for  ether,  over  which  he  supposed  it  to  possess  several  ad- 
vantages. Its  pharmacological  action  had  been  investigated  some 
months  earlier  by  Flourens,  but  Simpson  appears  to  have  made  his 
investigations  quite  independently.  Chloroform  soon  ousted  ether  in 
popular  favor  in  Europe,  and  although  in  America  a  considerable 
number  of  surgeons  continued  to  use  it,  ether  had  practically  fallen 
into  complete  disuse  throughout  Europe,  save  in  Lyons,  until  a  few 
years  ago.  The  continually  increasing  number  of  accidents  in  chloro- 
form anaesthesia  has,  however,  caused  a  reaction  to  set  in  in  favor  of 
ether,  and  it  seems  probable  that  it  will  once  more  be  reinstated  as  the 
rival,  and  perhaps  as  the  superior,  of  chloroform  throughout  the  world. 
Even  in  1880,  however,  Kappeler  could  write  that  in  Germany  chlo- 
roform was  used  exclusively. 

Many  attempts  have  been  made  to  introduce  other  substances  of  the 
methane  series  as  substitutes  for  the  two  generally  recognized  anaes- 
thetics, but  as  yet  no  other  has  attained  popular  favor.  Soon  after  the 
introduction  of  ether  and  chloroform,  nitrous  oxide  gained  a  perma- 
nent footing  as  an  anaesthetic  for  short  operations. 

These  anaesthetics  are  invariably  given  by  inhalation  and  not  by  the 
stomach,  as  it  is  found  that  the  exact  depth  of  the  narcosis  can  be 


154  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

much  more  easily  controlled  by  the  former  method.  Both  the  absorp- 
tion and  excretion  of  these  drugs  occur  almost  entirely  by  the  lungs, 
according  to  the  ordinary  physical  laws  of  the  absorption  of  gases  by 
fluids.  The  more  concentrated  the  vapor  of  chloroform  in  the  lungs, 
the  greater  is  the  quantity  absorbed  into  the  blood  and  the  deeper  the 
narcosis.  By  regulating  the  proportion  of  the  vapors  in  the  air  in- 
haled, therefore,  an  anaesthesia  of  any  desired  depth  may  be  induced. 
The  degree  of  narcosis  and  of  danger  is  not  indicated  by  the  actual 
amount  of  the  anaesthetic  which  has  been  used,  but  by  the  concentra- 
tion of  the  vapors  which  have  been  inhaled ;  one  patient  may,  in 
the  course  of  a  long  operation,  inhale  and  again  exhale  many  ounces 
of  chloroform  without  danger,  while  another  may  be  thrown  into  a 
position  of  extreme  peril  by  the  inhalation  of  a  few  drops  of  chloro- 
form in  concentrated  vapor. 

Symptoms. — The  action  of  chloroform  and  ether  may  be  divided 
into  three  stages  :  1,  that  of  imperfect  consciousness;  2,  that  of  ex- 
citement ;  3,  that  of  anaesthesia. 

The  first  effect  of  their  application  is  a  feeling  of  asphyxia,  which  is 
especially  marked  in  the  case  of  ether,  and  of  warmth  of  the  face  and 
head  and  eventually  of  the  whole  body.  The  senses  become  less  acute, 
the  patient  seeming  to  see  only  through  a  veil  of  mist,  and  the  voices 
of  those  in  the  immediate  neighborhood  appearing  to  come  from  a  dis- 
tance. Ringing,  hissing  and  roaring  in  the  ears,  and  a  feeling  of  stiff- 
ness and  of  inability  to  move  the  limbs  herald  the  approach  of  uncon- 
sciousness. With  the  exception  of  the  first  feeling  of  suffocation,  the 
sensations  are  generally  pleasant.  During  this  stage  the  face  is  gener- 
ally flushed,  the  pupils  enlarged,  the  pulse  is  somewhat  accelerated, 
and. the  respiration  may  be  rendered  irregular  by  the  sense  of  suffoca- 
tion, or  may  be  slightly  quickened.  Even  at  this  early  stage  sen- 
sation is  blunted. 

The  second  stage  of  excitement  varies  extremely  in  different  indi- 
viduals. In  some  cases,  especially  in  children,  it  is  entirely  absent, 
and  in  others  its  presence  may  be  indicated  merely  by  tremor,  by  the 
stretching  of  the  limbs,  or  by  irregularities  in  the  respiration,  but  in 
the  majority  of  cases  of  anaesthesia  it  is  much  more  marked.  It  often 
begins  by  movements  of  the  arms,  designed  either  to  push  away  the 
inhalation  mask  or  to  enable  the  patient  to  rise ;  soon  his  other  mus- 
cles are  involved  in  the  movement ;  he  struggles,  shouts,  sings,  groans, 
or  bursts  into  laughter.  The  movements  are  not  generally  uncoor- 
dinated, but  are  evidently  the  result  of  some  dream-like  condition  of 
the  consciousness,  and  these  dreams  are  often  connected  with  the  opera- 
tion or  with  the  surroundings  of  the  patient  before  the  inhalation  began. 
They  are,  of  course,  determined  largely  by  his  natural  mode  of  thought 
— one  person  prays  aloud  and  sings  hymns  ;  another  abuses  the  surgeon, 
the  hospital  and  all  his  recent  surroundings,while  yet  another  is  overcome 
with  the  fear  of  impending  death  and  laments  his  unfortunate  position. 
In  this  stage  the  pulse  is  generally  quickened,  the  skin  is  flushed  and 


ETHER  AND  CHLOROFORM .  155 

often  cyanotic,  the  respiration  is  extremely  irregular  from  the  strug- 
gling, and  the  pupil  continues  somewhat  dilated.  If  the  anaesthetic 
be  pushed,  however,  the  movements  soon  become  less  powerful,  the 
muscles  relax  and  the  stage  of  anaesthesia  sets  in. 

In  the  third  stage,  the  face  assumes  a  calm,  death-like  appearance 
from  the  relaxation  of  the  muscles,  the  pupils  contract  somewhat  and 
do  not  react  to  light.  The  reflexes  disappear,  one  of  the  last  to  go 
being  the  closure  of  the  eyelids  on  touching  the  cornea.  The  pulse 
is  generally  somewhat  slow  and  weak ;  the  face  is  pale  in  chloro- 
form anaesthesia,  but  may  be  suffused  and  cyanotic  after  ether.  The 
respiration  is  slow  and  shallow,  but  regular.  This  stage  of  anaesthesia 
may  be  kept  up  for  hours  without  much  change  by  the  repeated  inha- 
lation of  small  quantities,  although  the  pulse  tends  to  become  weaker 
and  the  respiration  shallower  unless  the  greatest  care  be  exercised,  and 
the  body  temperature  invariably  sinks.  When  the  administration 
ceases,  the  patient  passes  again  through  the  excitement  stage,  which, 
however,  is  not  generally  as  violent,  although  it  may  be  more  pro- 
longed, and  then  often  sinks  into  sleep,  which  lasts  several  hours. 
Not  infrequently,  however,  instead  of  sleep,  nausea,  giddiness  and  vom- 
iting continue  for  some  time  after  the  recovery  of  consciousness. 

In  surgical  anaesthesia,  the  third  stage  is  often  interrupted  by  short 
intervals  of  semi-consciousness  and  slight  excitement  if  the  adminis- 
tration of  the  drug  be  occasionally  interrupted,  as  is  sometimes  ad- 
visable in  prolonged  operations. 

The  use  of  these  drugs  is  so  widespread,  and  the  indications  of 
danger  in  anaesthesia  are  so  important  that  a  more  detailed  account  of 
the  alterations  observed  during  their  use  in  the  human  subject  may 
be  inserted  here. 

The  pulse  is  often  somewhat  accelerated  before  anaesthesia,  owing  to 
the  anxiety  and  nervousness  of  the  patient,  and  in  the  first,  and  still 
more  the  second  stage,  a  further  acceleration  may  occur  from  the  same 
cause,  although  in  other  instances  marked  slowing  of  the  pulse  may 
set  in  here  from  reflex  stimulation.  When  the  stage  of  anaesthesia  is 
reached,  the  pulse  becomes  slower  and  weaker  than  normally,  and  this 
change  increases  with  the  depth  of  the  anaesthesia  produced.  It  re- 
mains perfectly  regular,  however,  in  ordinary  cases,  and,  in  fact,  un- 
less the  anaesthesia  has  reached  an  extremely  dangerous  stage.  In 
very  prolonged,  deep  anaesthesia  the  weakness  of  the  pulse  may  give 
rise  to  anxiety,  especially  if  the  temperature  of  the  body  is  very  low. 

The  respiration  is  generally  fairly  regular  until  the  second  stage, 
save  that  the  breath  may  be  held  for  some  time  owing  to  the  choking 
sensation,  and  a  deep  gasp  may  follow ;  coughing  is  occasionally  met 
with,  especially  in  the  first  stage  of  ether  anaesthesia.  In  the  second 
stage,  the  respiration  is  extremely  irregular  when  the  excitement  is 
violent.  The  respiratory  muscles  are  involved  in  the  general  convul- 
sive movements,  so  that  no  air  whatever  can  enter  the  lungs  for 
several  moments,  and  then  several  deep  gasps  may  follow  and  load 


156  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

the  blood  with  concentrated  vapor.  Daring  the  third  stage  the  res- 
piration becomes  regular  but  shallower  and  slower  than  before  the 
anesthetic  was  applied,  and  if  the  operation  be  prolonged,  the  weak- 
ness of  the  respiration  may  give  rise  to  alarm.  Large  quantities  of 
saliva  and  mucus  may  hinder  the  respiration  and  require  removal,  and 
a  common  occurrence  is  the  production  of  snoring  from  the  falling  back 
of  the  tongue,  and  this  may  also  require  attention. 

The  behavior  of  the  pupil  is  of  some  importance  in  anaesthesia. 
During  the  first  and  second  stages  it  is  generally  somewhat  dilated, 
but  as  soon  as  complete  unconsciousness  is  attained,  it  becomes  rather 
narrower  than  it  is  normally.  As  the  patient  recovers,  the  slight  dil- 
atation recurs,  and  if  the  respiration  and  circulation  be  dangerously 
weak,  this  dilatation  also  occurs  in  most  cases.  Dilatation  of  the  pupil 
in  the  stage  of  anaesthesia,  therefore,  indicates  danger,  unless  it  is 
accompanied  by  symptoms  of  returning  consciousness,  such  as  reflex 
movements  and  vomiting. 

Other  eye  symptoms  which  occur  in  some  cases  are  squinting  and 
more  or  less  rhythmic  movements  of  the  eyeball.  In  the  beginning  of 
the  narcosis  the  pupil  is  generally  directed  upward  and  is  covered  by 
the  upper  lid  as  in  ordinary  sleep,  but  later  it  returns  to  the  normal 
position  ;  curious  rolling  movements,  which  are  quite  independent  in 
the  two  eyes,  often  make  their  appearance  (Kappeler,  Hogyes). 

The  hyper  secretion  of  saliva  and  of  bronchial  mucus  is  much  more 
marked  in  ether  than  in  chloroform  anaesthesia.  Vomiting  occurs  so 
frequently  during  anaesthesia  that  it  may  be  looked  upon  rather  as  one 
of  the  attendant  phenomena  than  as  an  accident.  It  may  set  in  prac- 
tically at  any  time,  but  is  more  often  seen  in  the  late  than  the  early 
stages,  and  more  frequently  when  the  anaesthetic  is  applied  soon  after 
a  meal  than  when  the  stomach  is  empty. 

Action.  —  The  action  of  ether  and  chloroform  on  the  Central  Nervous 
System  is  evidently  similar  to  that  of  alcohol,  although  the  phenomena 
habitually  elicited  in  the  use  of  the  former  are  very  rarely  produced  by 
the  latter.  In  all  three  intoxications,  however,  there  may  be  observed 
the  stages  of  lessened  consciousness,  of  excitement,  and  of  total  uncon- 
sciousness. Alcohol  was  formerly  administered  in  very  large  quantities 
to  allow  of  surgical  procedure,  and  ether  has  not  infrequently  been  used 
as  a  habitual  intoxicant. 

These  anaesthetics  produce  the  same  progressive  paralysis  of  the  cen- 
tral nervous  system  as  alcohol,  commencing  with  the  highest  cerebral 
functions,  those  of  self-control,  and  passing  downwards  through  the 
lower  intracranial  divisions.  The  spinal  cord  is  affected  before  the 
medullary  centres,  which  are  the  last  part  of  the  central  nervous  sys- 
tem to  become  paralyzed.  Some  authorities  believe  that  the  motor 
areas  of  the  brain  are  first  stimulated  before  being  paralyzed,  but  it  is 
unnecessary  to  enter  upon  this  question  here,  as  it  has  been  discussed 
under  alcohol.  The  wilder  excitement  of  chloroform  and  ether  may 
be  due  to  the  greater  irritation  which  they  excite  in  the  periphery. 
It  may  be  remarked  that  the  depression  of  the  motor  areas  has  been 


ETHER  AND   CHLOROFORM. 


157 


FIG.  5. 


shown  experimentally  in  the  case  of  chloroform  and  ether,  a  much 
stronger  electric  stimulus  being  necessary  to  produce  movement  of  a 
limb  after  these  drugs  than  before  them  ;  their  excitability  by  the  elec- 
tric current  has  not  been  tested,  however,  during  the  excitement  stage. 
The  anaesthesia  is  not  produced  equally  rapidly  throughout  the  body, 
the  back  and  the  extremities  first  be- 
coming insensible,  then  the  genital  or- 
gans and  rectum  and,  last  of  all,  the 
parts  supplied  by  the  trigeminus.  The 
reflexes  of  the  spinal  cord  are  said  to 
be  first  increased  by  ether  and  chloro- 
form and  then  depressed  and  paralyzed, 
but  the  primary  increase  is  of  very  short 
duration  and,  in  fact,  it  is  open  to  ques- 
tion whether  it  occurs  at  all.  It  would 
seem  that  ether  and  chloroform  tend  to 
depress  the  sensory  functions  before  the 
motor.  For  Bernstein  found  in  some 
cases  that  if  chloroform  were  excluded 
from  a  section  of  the  spinal  cord  by 
destruction  of  part  of  the  pia  mater, 
reflexes  could  be  elicited  in  other  parts 
of  the  cord  by  the  irritation  of  sensory 
nerves  whose  cells  lay  in  the  protected 
area,  while  irritation  of  nerves,  the 
cells  of  which  were  exposed  to  the 
chloroform,  had  no  effect  (Fig.  5).  In 
the  protected  area  there  were,  of  course, 
both  motor  and  sensory  cells,  and  an  im- 
pulse reaching  the  protected  sensory 
cell  was  transmitted  to  the  neighboring 
and  also  to  more  distant  motor  cells. 
An  impulse  reaching  the  exposed  sen- 
sory cell,  on  the  other  hand,  was  not 
transmitted  to  the  motor  cells,  although 
these  were  shown  by  the  first  part  of  Diagram  of  the  spinal  cord.  A-B^n 

thp  pvnprimpnf  to  V>p  rnmnVilp  nf  cfirrmln  of  the  corcl  exposed  to  the  action  of chlo- 

,  CapaOLC  OI  StimUla-  roform,  S-C  part  unaffected.     A  sensory 

tion.       Later,  however,    the    motor    Cells  ™pr^sion  traveling  by  the  posterior  root 

.                        V-V.AAO  fibre  #  does  not  elicit  a  reflex  movement, 

are     also     paralyzed,     as     IS     shown     by  but  one  reaching  the  cord  through  the  un. 

i    , .            /»  .  i                 -IT         .                    nn  affected   root    E  causes  reflex  impulses, 

Stimulation  OI  the   COrd  having:  no  enect,  which  may  be  sent  out  by  the  motor  cells 

i           ,1                  ....     °.,,           .  F,  Fin.  the  unaffected  area,  or  bv  F'  F' 

even  When  the   respiration  IS  Still  active,  in  the  poisoned  area.     The  cells  of ;the  an- 

T?1/A/-.fw/^ol    n4-Jw,,,l«±*^         ^f     4-V.                  U      1  terior  horns  F.  F'  and  the  dendrites  sur- 

Llectncal    Stimulation     Ot      the     Cerebral  rounding  them  are,  therefore,  intact  after 

motor  areas  produces  movement  for  some  po?nrteflex  arc  is  interruPted  atsorae other 
time  after  sensation  has  been  lost, but  as 

the  anaesthesia  becomes  deeper,  their  irritability  disappears.  Finally 
the  medullary  centres  are  also  paralyzed  by  the  anaesthetic.  Some 
authorities  have  stated  that  they  are  first  stimulated  directly  by  chloro- 
form and  ether,  but  the  evidences  for  this  will  be  discussed  later  (page 


158  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

162).  The  medullary  centres  are  liable  to  be  affected  by  reflex  stimu- 
lation up  to  the  moment  at  which  they  cease  to  send  out  impulses,  for 
the  respiratory  centre  responds  to  stimulation  of  the  superior  laryn- 
geal  nerve  as  long  as  the  respiration  continues.  It  is  possible  that  the 
motor  cells  are  not  directly  paralyzed  by  the  drug,  but  can  only  send 
out  impulses  received  from  the  sensory  cells,  and  that  the  paralysis  of 
these  is  the  cause  of  the  asphyxia. 

Shortly  stated,  the  direct  action  of  chloroform  and  ether  on  the  cen- 
tral nervous  system  is  a  descending  depression  and  paralysis  which 
affects  the  medullary  centres  last  of  all,  and  which  probably  affects  the 
sensory  and  receptive  functions  sooner  than  the  motor  ones. 

The  action  of  chloroform  and  ether  on  the  Respiratory  Centre  is 
partly  direct  and  partly  indirect.  In  the  first  stage,  the  respiratory 
movements  may  be  slowed  or  stopped  temporarily  by  a  reflex  action 
set  up  by  the  irritation  of  the  terminations  of  the  trigeminus  in  the 
nose  and  throat  and  of  the  pneumogastric  in  the  larynx  and  bronchi, 
but  this  interruption  is  only  of  short  duration  (Fig.  6).  During  the 


FIG. 


A  B  Gt 

Tracings  of  the  blood-pressure  (upper)  and  of  the  respiration  (lower)  of  a  cat  at  the  beginning  of 
ether  inhalation.  A,  normal  respiration.  At  B,  ether  inhaled,  and  there  follows  an  immediate  slow- 
ing of  the  respiration  (reflex  inhibition)  culminating  in  gasping  at  C.  The  respiratory  traciug  then 
resumes  its  normal  appearance  except  for  some  slowing  (central). 

second  stage  the  respiration  is  often  rendered  irregular  by  the  convul- 
sive struggling,  which  produces  alternately  periods  of  asphyxia  and 
deep  gasping  movements.  During  the  third  stage,  the  respiration  is 
regular  and  no  reflex  disturbance  occurs,  because  the  sensibility  is  so 
dulled  that  the  continued  irritation  of  the  nerve  ends  causes  no  reflex 
response.  In  this  stage,  however,  the  direct  action  of  the  drug  on  the 
centre  makes  itself  manifest  in  the  slow  and  shallow  respiratory  move- 
ments. If  the  drug  be  pushed,  the  weakness  and  slowness  of  the 
movements  increase,  until  the  respiration  ceases  entirely  from  paralysis 
of  the  centre ;  in  addition  to  its  direct  action  on  the  centre,  chloroform 
depresses  the  respiration  in  deep  anaesthesia  by  inducing  anaemia  of  the 
medulla  through  its  effects  on  the  circulation.  In  man  and  the  dog  and 
cat  the  respiration  is  gradually  extinguished,  but  in  the  rabbit  the  final 
standstill  is  preceded  by  very  rapid  and  extensive  respiratory  movements. 
The  effects  of  the  anaesthetics  on  the  Circulation  are  complicated  by 
the  respiratory  action,  and  in  order  to  arrive  at  any  satisfactory  con- 
clusions as  to  the  changes  in  the  heart  and  vessels,  it  is  therefore  neces- 
sary to  examine  their  action  while  the  aeration  of  the  blood  is  carried 
on  artificially,  when  the  effects  are  seen  to  be  partly  direct  and  partly 
indirect.  The  first  change  observed  in  the  blood-pressure  tracing, 


ETHER  AND   CHLOROFORM. 


159 


after  chloroform  or  ether  is  often  a  slowing  or  even  a  temporary  stand- 
still of  the  heart,  due  to  reflex  stimulation  of  the  inhibitory  centre 
from  the  irritation  of  the  air  passages  ;  but  in  other  cases  a  short  rise 
in  the  blood-pressure  is  seen  from  a  similar  reflex  action  on  the  vaso- 
motor  centre  and  this  may  be  accompanied  by  extreme  acceleration  of 
the  pulse  arising  from  the  general  excitement.  Later,  however,  a  fall 

FIG.  7. 


lJtH^J^^^^^-Artrt^^ 

Gradual  fall  of  the  blood-pressure  in  a  cat  during  anaesthesia  with  dilute  chloroform  vapor.  At  A, 
normal  pressure.  B,  inhalation  commenced  and  the  pressure  slowly  falls  soon  afterwards.  C,  blood- 
pressure  5  minutes  after  B.  D,  10  minutes  after  B.  E,  13%  minutes  later.  At  E,  the  respiration 
has  ceased,  but  the  blood-pressure  is  still  fairly  high  and  the  pulse  is  satisfactory.  Below  the  time  is 
marked  in  seconds. 

in  blood-pressure  is  observed,  and  afterwards  a  distinct  slowing  of  the 
heart.  Eventually,  if  the  administration  be  carried  far  enough,  the 
blood-pressure  falls  to  zero  and  the  heart  ceases  to  beat.  The  way  in 
which  this  fall  in  the  blood-pressure  is  produced  has  been  the  subject 
of  prolonged  discussion,  but  it  is  now  generally  recognized  that  the 
weakness  of  the  heart  is  the  chief  factor  and  that  along  with  this  there 

FIG.  8. 


Sudden  and  dangerous  fall  in  the  blood-pressure  from  the  inhalation  of  too  concentrated  vapor  of 
chloroform  during  anaesthesia  in  a  cat.  At  A  the  concentrated  vapor  began  to  be  inspired.  At  B  the 
blood-pressure  had  fallen  to  about  one  third  of  the  height  at  A,  and  the  pulse  was  so  weak  as  to  be 
scarcely  perceptible.  The  chloroform  mask  was  removed,  and  at  C  artificial  respiration  was  com- 
menced when  the  pulse  rapidly  improved  in  strength  and  the  pressure  began  to  rise. 

is  dilatation  of  the  peripheral  vessels.  The  blood-pressure  in  man 
has  been  found  to  be  reduced  by  chloroform  even  in  the  earlier  stages, 
and  in  deep  anaesthesia  the  fall  may  be  very  marked.  Under  ether  the 
pressure  rises  slightly  in  the  first  and  second  stages,  partly  from  the 
reflexes  arising  from  the  local  irritation,  and  partly  from  the  muscular 
movements.  During  complete  anaesthesia  it  falls  again  to  slightly 
above  the  normal  or  a  few  millimetres  below  it,  but  never  reaches  a 


160  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

point  indicating  grave  circulatory  disturbance  (Blauel,  Cook  and 
Briggs). 

Heart. — The  frog's  heart  under  chloroform  or  ether  beats  more 
slowly  and  more  weakly,  and  at  the  same  time  undergoes  a  certain 
amount  of  dilatation,  all  owing  to  the  paralyzing  effects  of  these  drugs 
on  the  cardiac  muscle.  About  48  times  as  much  ether  as  chloroform 
is  required  to  affect  the  frog's  heart,  however,  and  in  order  to  bring  it 
to  diastolic  standstill  36  times  as  much  ether  as  chloroform  must  be 
added  to  the  blood. 

The  effects  on  the  mammalian  heart  in  deep  anaesthesia  are  very 
similar.  The  slowing  is  not  so  marked,  however,  as  the  weakness  and 
the  dilatation,  so  that  the  rhythm  of  the  pulse  does  not  indicate  the 
extent  to  which  the  heart  is  affected.  The  auricles  are  acted  on  by 
smaller  quantities  than  the  ventricles,  and  the  former  may  be  rendered 
so  weak  as  to  give  practically  no  movement  to  an  attached  lever  long 

FIG.  9. 


Myocardiographic  record  of  the  movements  of  the  right  auricle  (upper  tracing)  and  right  ventricle 
(lower  tracing)  of  the  dog  daring  the  inhalation  of  concentrated  chloroform  vapor.  During  systole 
the  lever  attached  to  the  auricle  moves  from  D'  to  <S",  that  attached  to  the  ventricle  from  D  to  »ST  In 
diastole  they  return  to  D'  and  D  respectively.  At  A,  concentrated  chloroform  was  inhaled.  The  ex- 
cursion of  the  levers  towards  systole  rapidly  diminished,  wnile  that  of  the  ventricle  towards  D  was 
somewhat  augmented.  After  a  short  time  the  auricle  ceased  in  diastole,  while  the  ventricle  con- 
tinued to  beat,  though  much  weakened.  At  B,  the  chloroform  was  shut  off  and  the  heart  began  to 
recover  very  soon  afterwards. 

before  the  ventricular  force  is  very  seriously  impaired  (Fig.  9).  The 
first  direct  effect  of  these  drugs  on  the  heart,  therefore,  is  a  weakness 
in  the  auricular  contraction  and  an  increase  in  the  ventricular  relaxa- 
tion. The  diminution  in  the  strength  of  the  auricle  progresses  rapidly, 
while  the  ventricular  dilatation  soon  reaches  a  maximum  and  is  ac- 
companied by  lessened  force  of  contraction.  The  auricular  weakness 
soon  becomes  so  great  that  practically  no  blood  is  expelled  by  its 
systole,  and  the  slowing  of  the  heart,  which  has  not  been  very  marked 
up  to  this  point,  becomes  distinct.  The  ventricular  contractions  next 
become  extremely  weak  and  occasionally  fail  entirely,  and  soon  after- 
wards the  heart  comes  to  a  standstill  in  diastole.  Occasionally  a  venous 
pulse  appears  during  surgical  anaesthesia,  and  this  may  be  due  to  the 
dilatation  of  the  right  ventricle  causing  incompetency  of  the  tricuspid 


ETHER  AND  CHLOROFORM.  161 

valve.  The  mammalian  heart  suffers  under  extremely  dilute  chloro- 
form solutions  when  these  are  perfused  through  the  coronary  vessels. 
Thus  Sherrington  and  Sowton  found  that  blood  containing  0.01  per 
cent,  of  chloroform  exercised  a  distinctly  deleterious  effect  on  the 
heart,  and  about  0.05  per  cent,  of  chloroform  was  sufficient  to  arrest 
it.  Loeb  found  that  0.4  per  cent,  of  ether  in  blood  perfused  through 
the  heart  arrested  its  movements  in  a  few  minutes,  so  that  chloroform 
appears  to  be  at  least  eight  times  as  poisonous  to  the  mammalian  heart 
as  ether.  Ether  tends  to  dilate  the  coronary  vessels,  while  chloroform 
j-ather  constricts  them. 

This  direct  cardiac  action  of  chloroform  is  manifested  most  dis- 
tinctly in  the  third  stage  of  anaesthesia,  although  it  is  present  to  a 
slighter  degree  in  the  earlier  stages.  But  apart  from  this,  the  heart 
may  be  affected  earlier  by  inhibitory  activity,  and  this  is  of  the  gravest 
import  in  practical  anaesthesia  (Embley).  The  inhibitory  centre 
appears  to  be  thrown  into  a  state  of  abnormal  activity  and  the  irrita- 
tion of  the  air  passages  leads  to  reflex  inhibitory  impulses  being  sent 
to  the  heart,  which  responds  by  slowing  and  occasional  stoppage.  In 
the  normal  heart,  inhibitory  arrest  is  transient,  the  heart  only  pausing 
for  a  few  seconds  and  then  recommencing  its  contractions.  But  the 
heart  weakened  by  chloroform,  even  in  the  commencement  of  anaes- 
thesia, often  fails  to  recommence  beating  and  permanent  failure  of  the 
circulation  and  death  result  (Fig.  10).  This  has  been  demonstrated 

FIG.  10. 


Tracing  of  the  blood-pressure  in  a  dog  under  chloroform  (5  per  cent.)— sudden  slowing  of  the 
heart  and  fall  in  pressure  from  inhibitory  action  (Embley). 

experimentally  in  the  dog  (Embley)  and  accords  with  a  number  of 
observations  of  sudden  death  in  man.  It  is  liable  to  occur  in  the 
early  stages  when  concentrated  vapor  is  inhaled,  while  in  complete 
anaesthesia  the  vagus  centre  appears  to  be  less  irritable.  Ether  injures 
the  heart  less  than  chloroform,  and  this  fatal  inhibitory  arrest  has  not 
been  shown  to  be  induced  by  it. 
11 


162  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Vessels. — The  vascular  effects  of  the  anaesthetics  are  rendered  very 
difficult  of  investigation  by  the  presence  of  these  changes  in  the  heart. 
The  general  impression  has  been  that  the  tone  of  the  vaso-motor 
centre  is  lowered  and  that  the  blood-pressure  therefore  falls  through 
the  dilatation  of  the  vessels  along  with  the  weakness  of  the  heart ;  in 
deep  anaesthesia  this  depression  of  the  vaso-inotor  centre  is  probably 
elicited,  but  much  difference  of  opinion  exists  as  to  the  earlier  effects 
of  the  anaesthetics.  Thus  Scheinesson  observed  marked  dilatation  of 
the  vessels  of  the  rabbit's  ear  under  chloroform,  and  several  investi- 
gators found  the  reflex  irritability  of  the  vaso-motor  centre  diminished 
or  abolished  entirely  by  chloroform,  while  ether  had  less  effect  on  it. 
But  Gaskell  and  Shore  came  to  the  conclusion  that  chloroform  pri- 
marily stimulates  the  vaso-motor  centre,  and  this  is  confirmed  by 
Embley's  experiments.  This  stimulation  results  in  some  constriction 
of  the  vessels,  but  there  is  no  increase  in  the  blood-pressure  as  the 
narrowing  of  the  vessels  is  more  than  counterbalanced  by  the  weak- 
ness of  the  heart.  The  effects  of  ether  on  the  vaso-motor  centre  have 
not  been  the  subject  of  such  careful  research,  but  it  seems  probable 
that  they  are  similar  to  those  of  chloroform. 

As  regards  the  effect  on  the  vessel  walls  directly,  Embley  argues 
that  chloroform  relaxes  the  muscle  and  thus  widens  the  arterioles.  On 
perfusing  blood  containing  chloroform  through  the  vessels  of  isolated 
organs,  however,  it  is  generally  found  to  cause  some  narrowing  of 
their  calibre,  while  ether  is  said  to  dilate  them  slightly.  It  is  pos- 
sible that  the  vessels  of  the  different  organs  react  differently,  for  Pick 
states  that  the  circulation  in  the  extremities  is  slowed,  while  that  of 
the  abdominal  organs  is  accelerated  under  anaesthetics.  The  cerebral 
vessels  are  generally  found  to  be  narrowed  during  anaesthesia,  but  this 
is  probably  due  to  the  changes  in  the  general  blood-pressure  and  does 
not  indicate  any  direct  action  on  them. 

A  marked  dilatation  of  the  skin  vessels  occurs  in  the  first  stage  of 
anaesthesia,  and,  in  the  case  of  ether  at  any  rate,  generally  persists 
throughout ;  this  is  probably  due  to  some  central  action,  but  here,  as 
in  many  other  similar  instances,  the  primary  dilatation  of  the  cuta- 
neous vessels  has  not  been  fully  explained. 

Kemp  has  recently  drawn  attention  to  a  marked  contraction  of  the 
renal  vessels  of  the  dog  without  a  corresponding  increase  in  the  general 
blood-pressure  during  deep  ether  anaesthesia,  which  lessens  the  secre- 
tion of  urine  and  may  arrest  it  completely,  or  cause  such  injury  to 
the  kidney  that  albuminuria  or  even  haematuria  may  follow.  Some 
writers  state  that  albumin  is  found  in  the  urine  in  a  considerable  pro- 
portion of  cases  of  ether  anaesthesia  in  man,  which  would  suggest  that 
a  corresponding  action  is  elicited  here,  but  others  have  failed  to  detect 
any  change  except  a  slight  diminution  of  the  urine.  The  discrepancy 
in  these  results  may  perhaps  be  due  to  the  method  of  administration. 
Ether  is  often  given  in  such  a  way  as  to  induce  partial  asphyxia  and 
this  may  induce  contraction  of  the  renal  vessels  without  a  correspond- 
ing rise  in  the  blood-pressure. 


ETHER  AND   CHLOROFORM.  163 

The  Muscles  and  Nerves  are  not  affected  by  chloroform  or  ether  when  in- 
haled, but  when  a  frog's  muscle  is  exposed  to  an  atmosphere  of  either  of 
them,  it  is  weakened,  loses  its  irritability  and  eventually  passes  into  rigor 
mortis  ;  Eisenmeyer  and  Buchheim  found  that  the  relaxation  of  muscle  after 
contraction  was  somewhat  retarded  by  exposure  to  dilute  vapor  of  chloro- 
form. Waller  has  recently  shown  that  when  a  frog's  nerve  is  exposed  to 
chloroform  or  ether  vapor  in  weak  dilution,  its  irritability  is  at  first  increased  ; 
strong  vapor,  on  the  other  hand,  abolishes  the  excitability  temporarily  in 
the  case  of  ether,  generally  permanently  in  that  of  chloroform,  which  is 
much  the  more  powerful  nerve  poison  of  the  two.  The  sensory  fibres  are 
said  to  be  paralyzed  sooner  than  the  motor  when  chloroform  or  ether  is  ap- 
plied to  a  mixed  nerve  (Pereles  and  Sachs),  and  some  motor  fibres  of  a  trunk 
may  remain  unaffected,  while  others  are  paralyzed  ;  this  may  be  due  to  the 
anatomical  arrangement  (Albanere),  but  is  probably  the  result  of  some  funda- 
mental difference  in  the  fibres.  The  local  paralyzing  effects  of  ether  have  been 
elicited  repeatedly  in  the  human  subject  by  its  subcutaneous  injection,  and  have 
occasionally  been  followed  by  neuritis  and  permanent  weakness. 

Chloroform  and  ether  dissolve  the  Red  Corpuscles  and  free  the 
haemoglobin  when  they  are  shaken  with  defibrinated  blood  outside  the 
body,  and  chloroform  is  said  to  retard  the  reduction  of  oxy haemoglobin 
by  forming  a  loose  combination  with  it ;  Da  Costa  holds  that  ether 
tends  to  destroy  the  red  cells  during  anaesthesia  and  advises  caution  in 
its  administration  in  cases  in  which  a  diminution  in  their  numbers  may 
be  of  serious  import.  Apparently  chloroform,  when  absorbed,  exists 
not  in  simple  solution  but  in  loose  combination  with  the  cholesterin  and 
lecithin  of  the  red  corpuscles  and  with  the  proteids  of  the  plasma 
(Moore  and  Roaf).  The  blood  therefore  takes  up  chloroform  and 
ether  in  much  larger  quantities  than  water  or  saline  solution. 

The  eifects  of  chloroform  and  ether  on  the  Pupil  present  some  varia- 
tion in  different  animals,  and,  indeed,  are  not  very  constant  in  man. 
Xo  entirely  satisfactory  explanation  of  their  mechanism  has  been 
offered  as  yet.  The  dilatation  of  the  pupils  in  the  first  and  second  stages 
is  merely  the  accompaniment  of  the  general  excitement  and  anxiety,  and 
is  not  specific.  The  contraction  in  the  stage  of  unconsciousness  is  similar 
to  that  seen  in  natural  sleep,  and  is  evidently  of  central  origin.  It  may 
perhaps  be  a  secondary  effect  of  the  dilatation  of  the  vessels  in  the  iris 
(Limbourg).  The  dilatation  occurring  during  wakening  or  vomiting 
is  evidently  caused  by  the  same  process  as  that  of  the  preliminary 
stages.  Just  before  death  the  pupil  dilates,  and  this  may  perhaps  be 
attributed  to  the  effects  of  asphyxia  on  the  muscle  of  the  iris,  and  is 
so  frequently  observed  in  death  from  other  causes  that  it  cannot  be 
regarded  as  a  direct  result  of  the  chloroform. 

The  local  effects  of  the  anaesthetics  on  the  Alimentary  Canal  and 
Respiratory  Passages  are  confined  to  irritation  with  resultant  reflexes. 
Thus  the  profuse  secretion  of  saliva  and  of  mucus  is  due  to  the  irri- 
tation causing  increased  activity  of  the  glands  reflexly,  and  can  be 
arrested  by  atro'pine.  It  has  been  stated  that  the  bronchial  rhonchi 
are  due  entirely  to  aspirated  saliva,  but  this  is  incorrect,  as  they  occur 
in  animals  to  which  the  anaesthetic  has  been  given  through  a  tracheal 
canula.  The  irritation  is  much  greater  when  concentrated  ether  fumes 
are  inhaled  than  in  ordinarv  chloroform  anaesthesia. 


164  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

This  local  irritation  may  explain  in  part  the  vomiting  which  is  so 
often  a  feature  of  anaesthesia.  The  irritant  vapors  reach  not  only  the 
throat,  but  also  the  stomach  with  the  mucus  swallowed,  and  irritation 
of  either  of  these  parts  may  well  lead  to  reflex  vomiting.  But  similar 
effects  are  occasionally  induced  by  other  methods  of  anaesthesia,  such 
as  by  nitrous  oxide,  in  which  local  irritation  can  play  no  part,  so  that 
there  is  probably  some  central  effect  in  addition.  The  ordinary  move- 
ments of  the  stomach  and  intestine  do  not  seem  to  be  influenced  by 
anaesthesia,  unless  when  it  is  accompanied  by  asphyxia,  when  the  peri- 
stalsis may  be  increased. 

The  Kidney  appears  to  be  affected  in  a  certain  proportion  of  cases 
of  anaesthesia  in  man  as  is  shown  by  the  appearance  of  albumin  in  the 
urine.  Chloroform  induces  typical  fatty  degeneration  occasionally, 
while  the  albuminuria  after  ether  has  been  ascribed  to  a  specific  vas- 
cular change  by  Kemp.  The  proportion  of  cases  in  which  this  organ 
is  affected  seems  to  vary  extraordinarily,  some  authorities  finding  albu- 
minuria in  30  per  cent,  of  the  cases  where  chloroform  was  used ; 
while  others  could  detect  it  in  less  than  8  per  cent.  Most  surgeons 
consider  chloroform  far  more  deleterious  to  the  kidney  than  ether. 

The  Uterine  Contractions  during  parturition  seem  little  influenced  by 
moderate  anaesthesia,  but  are  slowed  in  the  deeper  stages,  probably 
because  the  anaesthetics  lessen  the  irritability  of  the  spinal  cord. 
Chloroform  and  ether  pass  into  the  foetal  blood,  and  some  experi- 
ments are  recorded  in  which  the  foetus  was  killed  by  the  inhalation, 
while  the  mother  recovered.  This  may  be  caused  either  by  the  direct 
action  of  the  drug  on  the  young  animal,  or  by  the  low  maternal  blood- 
pressure  leading  to  its  asphyxia.  It  does  not  seem  dangerous  to  in- 
duce a  moderate  degree  of  anaesthesia  during  labor  in  human  beings, 
although  here,  too,  the  effects  on  the  child  are  shown  by  an  increase  in 
the  nitrogen  excretion  in  the  urine  for  some  days. 

The  Temperature  falls  during  anaesthesia  of  even  short  duration. 
Thus  Kappeler  found  it  reduced  0.2-1.1°  C.  when  chloroform  was  in- 
haled 15-40  minutes,  and  a  fall  of  3-5°  C.  has  been  observed  during 
very  long  anaesthesia.  This  action  is  due  partly  to  the  greater  output 
of  heat  through  the  dilated  skin  vessels,  but  mainly  to  a  lessened  heat 
production  from  the  diminished  muscular  movement.  It  is  not  neces- 
sary to  assume,  therefore,  as  some  writers  do,  that  the  anaesthetics  lessen 
the  heat  production  by  their  direct  effects  on  the  tissues  in  general. 

Of  late  years  a  good  deal  of  interest  has  been  manifested  in  the 
effects  of  the  anaesthetics  on  the  Metabolism  of  the  tissues,  and  it  is  now 
generally  recognized  that  chloroform,  in  addition  to  its  action  on  the 
central  nervous  system,  produces  marked  changes  in  the  nutritive  proc- 
esses of  protoplasm.  The  simpler  organisms,  which  are  devoid  of 
nervous  structure,  are  killed  in  comparatively  dilute  solutions,  and 
chloroform  water,  therefore,  prevents  or  retards  putrefaction  and  the 
fermentation  of  yeasts.  It  seems  to  hinder  the  action  of  some  fer- 
ments, such  as  pepsin  and  rennet  ferment,  when  added  in  comparatively 
large  quantities,  but  increases  their  activity  in  greater  dilution.  Plants 


ETHER  AND   CHLOROFORM.  165 

cease  to  assimilate  carbonic  acid,  but  are  not  killed  by  chloroform 
except  in  very  large  quantities.  In  the  higher  animals  and  in  man, 
evidences  of  an  alteration  in  the  processes  of  life  and  nutrition  of  the 
different  organs  have  also  been  discovered,  quite  apart  from  the  effects 
on  the  nervous  system.  Thus  fatty  degeneration  l  of  various  organs  is 
produced  by  chloroform  administered  repeatedly  and  even  by  single 
inhalations  in  some  cases.  The  organs  implicated  in  this  change  are 
the  liver,  heart  and  kidneys  more  especially,  but  degeneration  of  ordi- 
nary muscle  has  also  been  observed  occasionally.  If  this  process 
attains  a  certain  degree  of  development,  it  may  lead  to  failure  of  the 
heart,  but  otherwise  the  tissues  recover  in  the  course  of  a  few  days. 
Traces  of  fatty  degeneration  have  been  observed  after  prolonged  ether 
narcosis  also,  but  they  are  so  slight  that  no  significance  attaches  to 
them  from  a  practical  point  of  view  (Selbach).  Given  in  small 
quantities  for  several  months,  chloroform  leads  to  atrophic  cirrhosis 
of  the  liver,  and  to  a  less  extent  of  the  kidneys,  spleen  and  lungs,  this 
cirrhotic  change  forming  a  sequel  to  a  preliminary  fatty  degeneration 
of  the  parenchymatous  cells.  Some  jaundice  occasionally  occurs  after 
chloroform  anaesthesia,  and  in  one  case  acute  yellow  atrophy  of  the  liver 
seemed  to  be  induced  by  it.  Ether  has  no  such  effect.  (Bandler.) 

Other  symptoms  of  disordered  nutrition  are  obtained  from  the  urine 
secreted  during  and  after  the  administration  of  chloroform  either  by 
inhalation  or  by  the  stomach.  The  nitrogen  eliminated  is  considerably 
increased,  and  the  sulphur  shows  a  similar  augmentation,  and  these 
would  seem  to  indicate  an  increased  destruction  of  nitrogenous  (pro- 
teid)  bodies  in  the  tissues.  In  the  normal  urine,  the  sulphur  appears 
partly  in  the  form  of  sulphates,  partly  in  forms  in  which  it  has  under- 
gone less  complete  oxidation.  After  chloroform  the  proportion  of  these 
constituents  is  changed,  the  unoxidized  sulphur  forming  a  much  larger 
part  of  the  total  than  normally,  and  apparently  occurring  in  a  substance 
nearly  allied  to  cystin.  (Kast  and  Mester.)  This  indicates  that  while 
the  breaking  up  of  the  nitrogenous  tissues  is  greater  than  normal, 
the  oxidation  is  not  so  perfect,  and  another  fact  pointing  in  the  same 
direction  is  the  not  infrequent  occurrence  of  acetone  in  the  urine  and 
breath  and  of  glycosuria.  (Becker.)  It  has  long  been  recognized  that 
diabetes  is  liable  to  be  aggravated  by  chloroform  anesthesia,  and 
some  fatalities  after  chloroform  seem  due  to  this  action.  The  sugar 
of  the  blood  has  been  found  to  be  increased,  and  the  glycogen  of  the 
liver  is  diminished  or  entirely  absent  after  chloroform ;  this  is,  ac- 
cording to  Paton,  the  effect  of  a  specific  action  on  the  liver  cells,  which 
form  glycogen  into  sugar  much  more  rapidly  than  usual ;  ether  has  a 
very  much  less  powerful  action  on  them.  Bile  pigment  is  said  to  occur 
in  the  urine  in  a  considerable  number  of  cases  of  anesthesia  with 
chloroform,  especially  one  or  two  days  after  the  administration.  The 
uric  acid  of  the  urine  is  augmented. 

These  effects  of  chloroform  on  the  metabolism  resemble  very  closely 

1  The  same  divergent  views  are  held  in  regard  to  the  nature  of  this  "  degeneration  " 
as  in  the  case  of  phosphorus,  to  the  chapter  on  which  the  reader  is  referred. 


166  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

those  of  phosphorus  poisoning,  and  have,  like  them,  been  ascribed  to 
the  formation  of  acid  in  excess  in  the  tissues.  They  seem  to  occur 
only  after  those  substances  of  the  fatty  series  in  which  chlorine  is 
substituted,  ether  having  little  or  no  effect  in  producing  fatty  degen- 
eration or  in  changing  the  proportion  of  the  sulphur  compounds  in 
the  urine. 

Immunity. — Anaesthesia  with  chloroform  or  ether  reduces  the  resist- 
ance of  the  tissues  and  renders  animals  more  susceptible  to  the  invasion 
of  bacteria  and  to  the  action  of  toxins. 

Distribution  in  the  Body.  —  When  chloroform  or  ether  is  absorbed 
from  the  lungs,  it  is  carried  all  over  the  body  by  the  blood,  but  is  not 
equally  distributed  throughout  the  tissues.  It  has  been  mentioned 
already  that  a  loose  combination  exists  between  chloroform  and  the 
lecithin  and  cholesterin  of  the  red  cells,  and  it  was  to  be  anticipated 
that  those  organs  which  are  richer  in  these  constituents  would  contain 
larger  quantities  of  the  drug.  As  a  matter  of  fact,  both  chloroform 
and  ether  are  found  in  larger  quantities  in  the  brain  than  in  the  blood, 
liver  or  muscles,  which  is  in  conformity  with  the  theory  of  Meyer  and 
Overton  regarding  the  causation  of  narcosis  (page  128). 

The  Excretion  of  both  ether  and  chloroform  takes  place  mainly  by 
the  lungs.  Whenever  the  partial  pressure  of  the  vapor  in  the  alveoli 
falls  sufficiently  far  below  that  in  the  blood  to  loosen  the  combination 
between  the  anaesthetics  and  the  constituents  of  the  blood,  the  drug 
diffuses  back  into  the  alveoli,  and  thence  passes  into  the  air.  Most  of 
the  anaesthetic  is  eliminated  very  rapidly,  but  traces  of  chloroform  are 
said  to  be  found  in  the  breath  for  24  hours  after  the  inhalation  and 
even  longer  in  cases  in  which  there  is  a  tenacious  mucous  secretion  from 
the  bronchi.  As  far  as  is  known  this  is  the  only  wa,y  in  which  ether 
is  excreted,  but  small  quantities  of  chloroform  escape  by  other  channels, 
for  it  has  been  found  in  the  urine,  and  is  said  to  occur  in  the  perspira- 
tion and  the  milk.  Some  of  the  chloroform  inhaled  seems  to  undergo 
combustion  in  the  body,  for  Kast  found  the  chlorides  of  the  urine  con- 
siderably increased  after  its  inhalation.1  The  acidity  of  the  urine  is 
also  augmented,  owing  to  the  hydrochloric  acid  formed  by  the  com- 
bustion. Bongers  has  found  traces  of  chloroform  in  the  stomach  after 
its  subcutaneous  injection. 

Differences  Between  Chloroform  and  Ether.  —  Ether  and  chloroform 
resemble  each  other  closely  in  their  general  effects,  but  differ  in  certain 
points  of  importance.  Thus  ether  has  a  much  weaker  narcotic  action 
than  chloroform,  for  Spenzer  found  that  1.5—2.5  volumes  per  cent,  of 
ether  vapor  in  air  produced  only  incomplete  anesthesia,  that  3—3.5  per 
cent,  induced  narcosis  in  25,  and  4.5  per  cent,  in  15  minutes,  while  6 
per  cent,  stopped  the  respiration  within  ten  minutes ;  Rosenfeld  ob- 
tained no  narcosis  with  0.5-0.7  volume  per  cent,  of  chloroform,  com- 
plete narcosis  with  1  per  cent,  only  after  30-45  minutes,  and  respiratory 
standstill  with  1.5  per  cent,  in  the  course  of  f-2  hours  after  theinhala- 

1  It  is  stated  that  chloroform  in  the  course  of  its  destruction  forms  traces  of  carbon 
monoxide,  which  may  be  recognized  in  the  expired  air. 


ETHER  AND  CHLOROFORM.  167 

tion  commenced.1  So  that  chloroform  is  about  3— 3  J  times  as  depress- 
ant to  the  central  nervous  system  as  ether,  while,  on  the  other  hand,  its 
action  on  the  heart  is  at  least  8  times  as  great  as  that  of  ether.  Ether 
has  to  be  given  in  more  concentrated  form  to  produce  anaesthesia,  and, 
therefore,  produces  more  irritation  of  the  air  passages,  as  shown  by  the 
greater  secretion  of  saliva  and  mucus,  by  coughing,  and  by  the  sensation 
of  asphyxia.  Dreser  has  shown,  however,  that  if  air  containing  less  than 
6  per  cent,  of  ether  be  inhaled,  this  irritation  and  feeling  of  suffocation 
is  not  very  marked.  Anaesthesia  is  produced  with  greater  difficulty, 
more  slowly  and  often  less  perfectly  than  with  chloroform,  and  the 
stage  of  excitement  is  generally  more  violent  and  prolonged.  But  the 
pulse  is  not  nearly  so  much  affected  as  by  chloroform  ;  it  may  be 
somewhat  slower  than  usual,  but  is  full  and  strong.  The  concentra- 
tion of  chloroform  which  is  necessary  to  produce  anaesthesia  is  very 
close  to  the  concentration  which  causes  serious  impairment  of  the 
heart's  action,  while,  on  the  other  hand,  3J  per  cent,  ether  vapor  is  suffi- 
cient to  cause  narcosis,  but  a  very  much  stronger  concentration  is  re- 
quired to  cause  a  dangerous  condition  of  the  heart.  In  the  same 
way  the  difference  in  the  concentration  required  to  produce  anaes- 
thesia and  that  which  will  stop  the  respiration  is  very  much  smaller  in 
chloroform  than  in  ether,  and  the  anaesthetist  has  thus  more  leeway 
when  he  uses  the  latter.  The  changes  in  the  metabolism  following 
the  use  of  chloroform  are  not  produced  to  the  same  extent,  if  at  all,  by 
ether. 

Regarding  the  Choice  of  an  Anaesthetic  it  must  be  said  that  each  has 
its  advantages,  but  that  ether  is  less  liable  to  cause  dangerous  symp- 
toms than  chloroform,  and  ought,  therefore,  to  be  used  wherever  special 
circumstances  do  not  indicate  the  latter.  Chloroform  is  always  pre- 
ferred by  the  patient,  for  it  causes  less  irritation  and  less  feeling  of  suf- 
focation, and  it  is  often  preferred  by  the  surgeon  because  it  induces  an- 
aesthesia sooner  and  less  of  it  is  required.  In  cases  where  excitement 
is  to  be  avoided  as  much  as  possible,  or  in  which  a  very  deep  anaesthesia 
with  complete  muscular  relaxation  is  required,  and  in  irritable  condi- 
tions of  the  air  passages,  chloroform  ought  to  be  used  rather  than  ether. 
In  the  case  of  drunkards,  ether  sometimes  fails  to  induce  deep  anaesthe- 
sia, and  in  very  hot  climates  anaesthesia  with  ether  may  be  difficult  and 
unpleasant  to  induce  owing  to  its  rapid  evaporation,  so  that  in  these 
cases  chloroform  may  be  necessary.  Lastly,  where  artificial  lights  are 
necessary  (except  the  electric  incandescent),  or  where  the  actual  cautery 
is  to  be  used,  ether  is  dangerous  on  account  of  its  inflammability,  and 
chloroform  is  indicated.  On  the  other  hand,  chloroform  is  specially  con- 
traindicated  in  cases  of  fatty  change  of  the  heart  and  in  renal  disease. 
The  disadvantages  of  both  anaesthetics  may  often  be  avoided  by  in- 
ducing unconsciousness  by  chloroform  and  prolonging  it  by  small 
quantities  of  ether.  The  effects  of  the  prolonged  use  of  chloroform 
are  avoided  in  this  way,  and  at  the  same  time  the  excitement  is  less 

1  Other  investigators  have  found  different  absolute  values  from  these,  but  the  relative 
strength  of  ether  and  chloroform  is  generally  held  to  be  about  1  to  3.  (Honigmann. ) 


168  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

marked,  and  less  irritation  of  the  air  passages  is  elicited  than  if  the 
anaesthesia  had  been  induced  by  concentrated  ether  vapor. 

The  Dangers  of  Anaesthesia  are  caused  only  in  part  by  the  direct 
action  of  the  ether  or  chloroform,  for  fatal  accidents  have  occurred 
from  objects  such  as  false  teeth  or  tobacco  plugs  falling  into  the  air 
passages  and  causing  asphyxia,  while  vomited  matter  has  been  drawn 
into  the  larynx  in  some  cases.  Very  often  the  relaxation  of  its 
muscles  permits  the  tongue  to  fall  back  into  the  throat,  rendering  the 
breathing  labored  and  stertorous ;  this  is  at  once  relieved  when  the 
tongue  is  drawn  forward.  The  accumulation  of  saliva  and  mucus,  or 
blood  in  the  throat  may  lead  to  similar  symptoms.  In  these  accidents 
the  chloroform  or  ether  is  only  indirectly  the  cause,  but  in  a  large  and 
ever-increasing  number  of  cases,  the  fatal  effects  must  be  ascribed  to 
the  direct  action  of  the  anaesthetics.  The  proportion  of  accidents  during 
anaesthesia  is  very  difficult  to  estimate,  and  great  discrepancies  occur  in 
the  statistics  of  different  surgeons.  Thus,  in  one  of  the  London  hos- 
pitals, one  death  occurred  from  chloroform  in  1,236  cases  of  anaesthesia ; 
Juillard  gives  one  in  3,258,  McGuire  one  in  15,000,  as  the  proportion 
of  fatalities,  while  Lawrie  gives  a  series  of  over  40,000  cases  without 
a  single  death.  A  fair  average  would  seem  to  be  one  death  in  3,000 
chloroform  inhalations.  The  statistics  of  ether  fatalities  also  vary 
from  one  death  in  3,000  to  one  in  16,000  cases,  but  probably  one  in 
10,000—12,000  cases  would  represent  the  average  mortality.1 

A  very  prolonged  discussion  as  to  the  Cause  of  Death  in  these  cases 
has  been  carried  on,  and  even  now  there  cannot  be  said  to  be  any 
unanimity  of  opinion  on  the  subject.  A  fatality  may  occur  practically 
at  any  stage  of  the  anaesthesia,  and  the  accounts  of  its  onset  and  symp- 
toms differ  exceedingly.  In  the  majority  of  cases  it  is  stated  that  the 
pulse  suddenly  disappeared,  and  the  breathing  either  ceased  at  the  same 
moment  or  after  one  or  two  weak  inspirations.  In  others  the  respi- 
ration is  stated  to  have  ceased  before  the  pulse,  and  in  several  the 
heart-beat  could  be  felt  or  heard  after  the  pulse  ceased.  A  very  con- 
siderable proportion  of  the  fatalities  under  chloroform  occur  early  in 
the  anaesthesia,  often  before  the  operation  has  been  begun,  an,d  these 
have  generally  been  regarded  by  anaesthetists  as  due  to  a  reflex  arrest 
of  the  heart.  This  has  been  disputed  by  experimental  investigators, 
and,  as  in  these  accidents  it  is  impossible  to  make  exact  observations, 
owing  to  the  necessity  for  prompt  measures  for  resuscitation,  it  has 
often  been  denied  that  fatalities  occur  from  this  cause.  The  subject  has 
recently  been  the  subject  of  prolonged  research  by  Embley,  who  has 
triumphantly  vindicated  the  position  of  the  practical  anaesthetists  by 
showing  that  fatal  arrest  of  the  heart  may  occur  in  early  chloroform 
anaesthesia  through  excessive  inhibitory  action  upon  the  weakened 
heart.  This  danger  does  not  seem  to  be  caused  by  ether  to  the  same 
extent,  and  this  is  in  accordance  with  its  much  weaker  effects  on  the 
heart.  These  early  fatalities  in  chloroform  anaesthesia  are  due  in  part 

1  Gurlt's  careful  statistics  of  330,000  cases  of  anaesthesia  gave  a  mortality  of  1  in 
2,000  for  chloroform  and  1  in  5,000  for  ether,  but  these  both  seem  unusually  high. 


ETHER  AND  CHLOROFORM.  169 

to  the  chloroform  already  absorbed,  in  part  to  reflexes  arising  from  its 
irritant  action  and  from  the  excitement  and  struggling. 

But  fatal  accidents  may  occur  in  anaesthesia  from  chloroform  or 
ether,  by  the  action  on  the  organs  after  the  danger  of  reflexes  has  dis- 
appeared, from  the  depression  of  the  central  nervous  system.  The 
explanation  of  these  fatalities  has  been  much  disputed,  the  view  hav- 
ing prevailed  formerly  that  while  ether  paralyzed  the  respiration  with- 
out affecting  the  heart,  chloroform  acted  first  on  the  heart  and  para- 
lyzed it  before  the  respiratory  centre.  In  1889  some  criticisms  by  the  Lan- 
cet of  the  results  of  experiments  in  Hyderabad  led  the  Nizam  (Prince) 
of  that  province  to  appoint  a  commission,  including  Sir  Lauder  Brun- 

FIG.  11. 


Tracings  of  the  blood-pressure  (upper)  and  of  the  respiration  (lower)  of  the  cat  in  the  last  stage  of 
ether  anaesthesia,  failure  of  the  respiration.  At  Jf  the  ether  was  shut  off,  and  at  D  artificial  respira- 
tion was  begun.  The  oscillations  on  the  respiratory  tracings  after  D  are  due  to  the  artificial  respira- 
tion. The  heart  continues  to  beat  after  the  failure  of  the  respiration.  The  pulsations  increase  in 
size,  not  from  an  increase  in  the  strength  of  the  heart,  but  from  the  slowness  of  the  beat,  which  gives 
time  for  the  arteries  to  empty  themselves  between  each  pulse. 

ton,  to  investigate  the  question,  and  after  experimenting  on  over  600 
animals,  this  commission  came  to  the  conclusion  that  death  during 
chloroform  inhalation  is  always  due  to  arrest  of  the  respiration.  This 
decision  has  been  subjected  to  much  criticism,  and  there  is  no  question 
that  the  alterations  in  the  circulation  produced  by  chloroform  were  not 
properly  appreciated,  or,  at  any  rate,  were  not  sufficiently  emphasized 
in  the  report.  The  condition  when  the  breathing  fails  during  deep 
anaesthesia  varies  with  the  concentration  of  the  vapor.  If  very  dilute 
chloroform  or  ether  be  inhaled,  the  respiration  always  ceases  several 
minutes  before  the  heart,  which  continues  to  beat  fairly  strongly  at 
first  but  rapidly  becomes  weaker.  If  more  concentrated  vapor  be 
used,  the  respiration  again  ceases  before  the  heart,  which  is,  however, 
much  weakened  and  comes  to  a  standstill  after  a  short  interval ;  and 
as  the  concentration  is  increased,  the  wreakness  of  the  heart,  at  the  mo- 
ment when  the  respiration  fails,  also  increases,  and  the  interval  between 
the  arrest  of  the  respiration  and  of  the  heart-beat  becomes  shorter. 
Finally,  when  air  saturated  with  vapor  is  inhaled,  the  interval  between 
the  two  is  so  short  as  to  be  inappreciable  (Fig.  12).  When  concen- 
trated vapor  of  either  chloroform  or  ether  is  inhaled,  the  pulse  may 
be  so  weak  as  to  be  no  longer  perceptible  before  the  respiration 
ceases,  and  the  anaesthetist,  therefore,  believes  that  heart  failure  has 
been  the  cause  of  death,  but  if  the  movements  of  the  heart  be  regis- 


170  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

tered  directly,  it  is  found  beating  as  long  as  the  respiratory  movements 
are  carried  on.  The  importance  of  the  condition  of  the  heart  is  fur- 
ther shown  by  the  results  of  attempts  to  resuscitate  the  animal  after 
the  respiration  has  ceased  ;  for  if  artificial  respiration  be  commenced  at 
once,  the  animal  can  invariably  be  restored  to  life,  provided  the  heart 
has  not  been  weakened  too  much ;  but  if  concentrated  vapors  have 

FIG.  12. 


E 


Diagram  representing  the  state  of  the  heart  at  the  failure  of  respiration  from  an  anesthetic  (chloro- 
form or  ether).  A  represents  the  respiratory  movements,  which  cease  very  early  in  the  tracing  B 
the  pulsations  of  the  heart  at  this  point  if  the  anaesthetic  vapor  has  been  much  diluted  with  air,  C  if 
it  is  of  medium  strength,  I)  if  very  concentrated,  and  E  if  saturated.  The  heart  pulsations  are  recorded 
by  the  mercury  manometer. 

been  inhaled,  the  heart  is  unable  to  carry  on  the  circulation,  and  the 
animal  cannot  be  resuscitated. 

Hill  has  recently  pointed  out  that  the  failure  of  the  respiration  may 
be  caused  in  part  by  the  anaemia  of  the  central  nervous  system  from 
the  fall  in  blood-pressure.  The  weakness  of  the  heart  induced  by  chloro- 
form is  therefore  fraught  with  double  danger,  for  not  only  is  the  circu- 
lation imperiled  by  it  but  the  respiration  is  indirectly  weakened. 

From  a  practical  point  of  view,  it  is  of  comparatively  little  impor- 
tance whether  there  are  a  few  fluttering  beats  of  the  heart  after  the 
last  inspiration  or  not.  The  all -important  question  is  whether  the 
heart  has  been  so  injured  as  to  be  unable  to  carry  on  the  circulation, 
and  this  is  decided  by  the  concentration  of  the  vapor  that  has  been  in- 
haled. It  has  been  mentioned  already  that  ether  acts  very  much  less 
on  the  heart  than  chloroform,  and  this  is  really  the  reason  why  ether 
is  so  much  the  safer  anaesthetic.  Even  when  dilute  vapor  of  chloro- 
form is  inhaled,  the  heart  is  considerably  injured  when  the  respiration 
ceases,  while  unless  very  concentrated  ether  fumes  be  inhaled,  the 
weakness  of  the  heart  is  very  much  less.  In  the  inhibitory  cardiac 
arrest  also  the  concentration  in  which  the  chloroform  has  been  inhaled 
is  the  all-important  factor,  for  if  the  heart  has  been  seriously  damaged 
the  arrest  is  final,  while  when  less  concentrated  vapor  has  been  used 
the  heart  overcomes  the  inhibition  and  resumes  its  contractions. 

The  autopsy  in  cases  of  death  by  chloroform  or  ether  shows  no  spe- 


ETHER  AND  CHLOROFORM.  171 

cific  lesions.  The  blood  is  often  dark  colored  from  the  asphyxia,  and 
the  heart  is  found  dilated.  Irritation  of  the  respiratory  passages  may 
be  present  in  ether  poisoning,  and  the  odor  of  the  anaesthetic  may  be 
recognized  in  tiie  different  organs.  Microscopic  examination  may 
show  some  alterations  in  the  cells  of  the  respiratory  centre  and  cardiac 
ganglia,  fragmentation  of  the  heart  muscle,  and  some  degeneration  of 
the  liver,  kidneys,  spleen  and  heart  after  chloroform  (Poroschin). 

Apparatus  and  Principles.  —  The  principles  on  which  the  safe  pro- 
duction of  anesthesia  is  based,  then,  are  comparatively  simple,  but 
their  interpretation  into  practice  has  given  rise  to  various  methods. 
A  large  number  of  inhalers  have  been  introduced  with  the  object 
of  permitting  of  only  a  certain  degree  of  concentration  of  the  vapors. 
But  the  great  majority  of  these  are  entirely  erroneous  in  principle, 
the  concentration  of  the  vapor  being  determined  by  the  character 
of  the  respiration  of  the  patient,  and  the  number  of  accidents  has  not 
been  appreciably  reduced  by  their  use.  In  one  of  these,  the  amount 
of  oxygen  available  for  respiration  was  found  to  be  reduced  to  5  per 
cent.,  while  the  carbonic  acid  had  risen  to  7.8  per  cent,  after  two  min- 
utes' respiration.  This  mixture  of  gases  is  insufficient  to  support  the 
combustion  of  a  candle,  and  is  very  near  that  which  is  immediately 
fatal  to  animal  life.  In  another  the  concentration  of  the  vapor  was 
found  to  vary  between  1.2  and  16.4  volumes  per  cent.  Several 
apparatuses  have  recently  been  constructed  on  correct  principles,  which 
allow  of  an  exact  gradation  in  the  strength  of  the  vapor  inhaled,  but 
they  are  exceedingly  cumbrous,  and  while  they  might  be  used  in  hospi- 
tals, are  certainly  not  available  for  ordinary  practice.  The  advantage  of 
this  principle  of  measuring  the  concentration  of  the  vapors  is  further 
only  relative,  for  it  has  been  shown  that  vapors  so  dilute  as  to 
be  absolutely  safe  do  not  induce  anaesthesia  within  a  reasonable 
time.  Thus  1  per  cent,  chloroform  seems  to  be  absolutely  safe, 
but  no  surgeon  will  wait  J  — j  hr.  for  the  anesthetist.  To  induce 
anaesthesia,  therefore,  vapors  have  to  be  used,  which  would  in  time 
be  fatal,  and  only  after  the  reflexes  disappear,  is  it  possible  to 
reduce  the  concentration  to  the  point  of  absolute  safety.  The 
responsibility  of  the  anaesthetist  is,  therefore,  lessened,  but  by  no 
means  entirely  removed  by  these  methods.  In  the  vast  majority  of 
cases,  however,  much  simpler  apparatus  is  used,  and  the  ordinary  mask 
or  towel  on  which  the  anaesthetic  is  poured  is  not  responsible  for  a 
larger  proportion  of  accidents  than  the  more  complicated  forms  of  ap- 
paratus. When  no  inhaler  is  used,  the  anaesthetist  attempts  to  regulate 
the  concentration  of  the  vapor  according  to  the  symptoms,  and  this  can 
be  done  with  complete  success  by  watching  the  respiration  closely.  If 
the  breathing  be  shallow,  much  less  concentrated  vapor  is  inhaled  into 
the  alveoli  than  if  it  be  deep  and  gasping,  for  in  ordinary  respiration 
the  air  in  the  smaller  bronchioles  and  alveoli  is  not  exchanged  directly 
with  every  respiration,  but  only  by  a  process  of  diffusion  from  the 
larger  air  passages.  The  deeper  the  respiration,  however,  the  further 
does  the  vapor  penetrate  and  the  lower  the  concentration  needed  to 


172  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

change  the  quantity  in  the  blood.  An  experienced  anaesthetist,  by 
watching  the  respiration,  removing  the  mask  during  deep  breathing 
and  replacing  it  when  it  becomes  steady,  can  regulate  with  sufficient 
nicety. the  concentration  of  the  anaesthetic  in  the  alveoli  and  thereby 
the  quantity  in  the  blood.  When  anesthesia  has  been  attained,  he  of 
course  ceases  the  administration  until  the  return  of  the  reflexes  indicates 
awakening  consciousness,  and  even  then  applies  much  smaller  quantities 
than  were  necessary  at  first.  This  method  of  inducing  anaesthesia  re- 
quires the  anaesthetist  to  watch  only  the  respiration  and  the  reflexes, 
and  is  that  advised  by  Simpson  and  his  followers  (see  Hyderabad  Com- 
mission Report).  A  further  safeguard  has  been  sought  for  in  the  con- 
dition of  the  pulse,  and  this  would  seem  the  natural  consequence  of 
what  has  been  stated  above  as  to  the  importance  of  the  condition  of 
the  heart.  The  pulse,  however,  is  not  very  reliable  as  a  guide  in 
anaesthesia,  for  in  the  second  stage,  in  which  a  certain  number  of  fatal- 
ities occur,  it  is  quickened  by  the  excitement  and  may  be  irregular,  and 
only  gives  indications  of  danger  when  it  is  too  late  to  take  measures  to 
prevent  it.  In  the  third  stage  it  may  become  gradually  weaker,  and 
thus  indicate  approaching  danger,  but  if  the  respiration  be  watched 
the  warning  is  given  earlier.  A  large  number  of  anaesthetists  advise, 
however,  that  pulse  and  respiration  both  be  watched,  and  this  would 
seem  to  be  the  safest  method,  provided  always  that  the  anaesthetist  does 
not  depend  on  the  pulse  too  much  for  indications  of  danger,  and  does 
not  allow  it  to  distract  his  attention  from  the  more  important  indica- 
tions given  by  the  respiration. 

Preliminary  Examination.  —  Before  anaesthesia,  a  careful  examination 
should  be  made  of  the  condition  of  the  patient,  and  if  there  is  great 
anxiety  and  excitement,  a  hypodermic  injection  of  morphine  may  be 
given  beforehand,  or  chloral  may  be  prescribed,  but  these  are  rarely 
necessary.  Valvular  disease  of  the  heart  does  not  contraindicate  an 
anaesthetic  unless  there  are  marked  symptoms  of  inefficiency,  such  as 
dropsy  or  oedema.  In  fatty  disease  of  the  heart,  on  the  other  hand, 
chloroform  is  to  be  avoided,  and  if  it  seems  extensive,  ether  is  also 
dangerous  from  the  strain  put  on  the  circulation  during  the  excitement. 
Chloroform  is  liable  to  induce  fatty  degeneration  of  the  heart,  and  for 
this  reason  it  would  not  seem  advisable  to  use  it  in  successive  operations 
on  the  same  patient.  Atheromatous  arteries  are  dangerous  from  the 
tendency  to  apoplexy  during  the  second  stage  also,  and  if  anaesthesia 
is  absolutely  necessary,  an  opiate  ought  to  be  given  previously.  Anaes- 
thesia is  said  to  be  dangerous  in  cases  of  brain  tumor,  and  this  may 
possibly  arise  from  the  fragility  of  the  vessels.  In  cases  of  bronchitis 
and  catarrh  of  the  air  passages,  chloroform  is  to  be  preferred  to  ether 
as  it  is  less  irritating,  while  in  Bright' s  disease  chloroform  is  generally 
more  injurious  than  ether  from  the  resultant  albuminuria  and  tendency 
to  fatty  degeneration,  although  ether  is  also  believed  by  many  to  disturb 
the  renal  functions.  Advanced  diabetes  contraindicates  anaesthesia, 
the  sugar  increasing  in  the  urine  afterwards  and  coma  and  death  some- 
times supervening  in  the  course  of  a  few  days.  Da  Costa  recommends 


ETHER  AND   CHLOROFORM.  173 

that  where  there  are  symptoms  of  anaemia,  an  examination  of  the  blood 
should  be  made  before  anaesthesia,  and  states  that  where  the  haemo- 
globin is  found  to  be  deficient,  great  care  is  necessary  and  that  where 
it  is  lower  than  50  per  cent,  of  the  normal,  an  anaesthetic  is  contra- 
indicated. 

Practical  Anaesthesia.  —  The  patient  should  have  a  light,  easily  di- 
gested meal  2—4  hours  before,  so  that  the  stomach  may  be  empty  and 
vomiting  avoided  as  far  as  possible.  The  bowels  should  also  be  regu- 
lated the  day  before  for  the  same  reason.  He  should  then  be  laid  on 
a  table  of  suitable  height  with  a  low  pillow,  and  should  remove  false 
teeth  and  any  other  foreign  object  from  the  mouth.  The  clothing 
about  the  neck,  chest  and  abdomen  is  to  be  loosened  or  removed  to 
allow  of  perfectly  free  respiration,  but  warm  blankets  or  warm  bottles 
should  be  applied  as  far  as  possible  to  prevent  the  fall  of  temperature 
if  the  operation  is  likely  to  be  a  long  one.  The  eyes  are  closed  in 
order  to  protect  the  conjunctiva  from  the  irritating  vapor.  The 
anaesthetic  is  then  applied  on  a  towel  or  on  a  mask,  which  ought  to 
be  freely  permeable  by  the  air,  and  ought  not  to  fit  closely  to  the  face. 
It  must  be  remembered  that  the  air  passes  through  cloth  with  much 
greater  difficulty  when  it  is  wet  by  the  saliva  and  mucus,  and  that  a 
mask  which  is  freely  permeable  at  the  commencement  of  an  operation, 
may  lead  to  asphyxia  after  it  has  been  soaked  during  the  first  and 
second  stages.  The  patient  is  instructed  to  breathe  as  regularly  as 
possible,  or  to  count  from  one  upwards,  and  some  of  the  anaesthetic  is 
dropped  on  the  mask.  If  the  breath  be  held,  the  mask  should  be 
raised  a  little  from  the  face,  as  the  next  inspiration  will  be  a  very  deep 
one.  During  the  excitement  stage  the  respiration  is  irregular,  and 
great  care  must  be  taken  to  avoid  the  inhalation  of  too  concentrated 
vapor.  As  soon  as  the  conjunctival  reflex  disappears,  the  mask  is  re- 
moved, and  is  replaced  only  when  it  reappears  or  when  the  patient 
evinces  signs  of  pain.  Throughout  the  anaesthesia,  care  must  be  taken 
to  prevent  any  interference  with  the  respiration  by  the  operator  lean- 
ing on  the  thorax  or  abdomen.  Very  often  stertorous  respiration  sets 
in  from  the  tongue  falling  back  into  the  throat,  and  this  has  to  be 
remedied  by  pressing  forward  the  angle  of  the  jaw,  or  if  this  is  not 
sufficient,  by  pulling  out  the  tongue  with  a  blunt-pointed  forceps. 
Vomiting  is  a  very  common  occurrence  in  anaesthesia,  and  when  it  sets 
in,  the  head  is  turned  to  one  side  and  the  vomited  matter  removed 
with  a  sponge. 

A  more  serious  accident  is  the  failure  of  the  respiration.  A  reflex 
arrest  often  occurs  in  the  first  stage,  but  is  not  of  importance  in  itself, 
but  only  from  the  deep  gasping  inspiration  which  follows  it.  If  the 
anaesthetic  be  given  too  long  in  concentrated  form,  however,  the  res- 
piration fails  from  direct  action  on  the  centre,  and  this  demands  im- 
mediate attention.  The  head  ought  to  be  lowered  at  once,  and  the 
lower  limbs  elevated,  in  order  to  drive  the  blood  to  the  head  as  far  as 
possible  and  thus  remedy  the  anaemia  of  the  brain  from  the  weakness  of 
the  heart  that  accompanies  the  cessation  of  the  respiration.  The  epi- 


174  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

glottis  must  be  raised  by  pressing  forward  the  angles  of  the  jaw  (Hare), 
or  by  dragging  forward  the  base  of  the  tongue  with  hook  or  finger. 
Artificial  respiration  in  one  or  other  form  ought  to  be  commenced  at 
once,  and  carried  on  as  long  as  is  necessary ;  a  large  number  of  methods 
of  performing  artificial  respiration  have  been  proposed,  but  they  can 
only  be  taught  in  a  practical  class  and  need  not  be  entered  upon  here.1 
If  the  pulse  is  weak,  intermittent  pressure  over  the  heart  may  aid  it  in 
carrying  on  the  circulation,  and  it  has  been  proposed  to  pass  one  hand 
up  under  the  ribs,  and  then  press  the  heart  between  the  two  hands  and 
aid  it  in  expelling  its  contents.  If  the  heart  stops  at  this  stage,  there 
is  little  hope  of  reviving  the  patient,  although  this  can  often  be 
done  in  animals  by  kneading  the  heart  between  the  two  hands.  Various 
drugs  have  been  recommended  in  these  cases,  but  it  is  exceedingly 
questionable  whether  they  are  really  of  service  ;  alcohol,  ammonia  and 
ether  have  been  injected  subcutaneously,  and  may  conceivably  cause  such 
local  irritation  as  to  reinstate  the  respiration  reflexly,  although  this  is 
improbable.  Strychnine,  caffeine  and  atropine  have  been  injected  as  res- 
piratory stimulants,  and  digitalis  to  strengthen  the  heart  contraction  ;  as 
a  matter  of  fact,  however,  if  the  circulation  is  strong  enough  to  cause  the 
absorption  of  these  drugs  and  carry  them  to  the  respiratory  centre  and 
the  heart,  the  patient  will  recover  with  the  artificial  respiration  alone, 
while  on  the  other  hand,  they  are  of  no  value  unless  absorbed.  Nitrite 
of  arnyl  is  often  given  by  inhalation  in  cases  of  accident,  but  the  blood- 
pressure  is  so  low  already  that  there  really  seems  no  advantage  in  re- 
ducing it  further,  and  amyl  nitrite  can  have  no  other  action. 

Sudden  arrest  of  the  heart  is  the  most  dangerous  accident  of  anes- 
thesia, and,  as  Embley  has  shown,  is  due  to  inhibitory  stimulation  act- 
ing on  the  weakened  heart.  The  treatment  consists  in  inversion,  arti- 
ficial respiration,  and  massage  of  the  heart.  Atropine  should  be 
injected  in  order  to  paralyze  the  inhibitory  mechanism,  and  in  view  of 
the  arrest  of  the  circulation  it  might  be  thrown  into  the  heart  directly 
by  means  of  a  long  hypodermic  needle. 

In  the  course  of  very  long  operations  it  is  recommended  to  allow 
the  patient  to  almost  recover  consciousness  at  intervals,  but  this  is  often 
impossible  without  interfering  with  the  course  of  the  operation.  It 
must  be  remembered  that  In  prolonged  anaesthesia  comparatively  small 
quantities  are  required  to  maintain  unconsciousness  when  it  is  once 
completely  reached,  and  at  the  same  time  that,  owing  to  the  fall  of  tem- 
perature and  the  prolonged  action  of  the  drug,  the  quantity  necessary 
to  produce  cessation  of  the  respiration  and  the  heart  is  much  smaller 
than  during  shorter  operations.  In  order  to  induce  anaesthesia  within 
a  reasonable  time,  comparatively  strong  vapor  may  be  used  at  first, 
but  as  soon  as  unconsciousness  is  reached,  the  vapor  ought  to  be  diluted 
as  far  as  is  compatible  with  the  continuation  of  the  narcosis. 

On  the  completion  of  the  operation,  the  patient  seldom  requires  fur- 
ther attention  from  the  anaesthetist ;  after  prolonged  anaesthesia  heat 

1  For  a  comparison  of  the  efficacy  of  different  forms  see  Schafer,  Medico-Chirurgical 
Transactions,  vol.  Ixxxvi.,  supplement,  1904. 


ETHER  AND  CHLOROFORM.  175 

may  be  applied  by  warm  bottles,  etc.,  as  the  temperature  often  continues 
to  fall  for  some  time  after  the  administration  of  the  drug  has  ceased.  If 
vomiting  persists  after  the  recovery  of  consciousness,  ice  may  be  sucked, 
or  bismuth  may  be  prescribed.  The  inhalation  of  vinegar  has  been 
recommended  and  relief  is  sometimes  given  by  lavage  of  the  stomach. 

The  patient  should  always  be  placed  in  the  recumbent  position  when 
possible,  as  otherwise  the  weakened  heart  tends  to  drive  the  blood  in  the 
direction  of  least  resistance,  that  is,  downwards,  and  in  the  depressed 
condition  of  the  vaso-motor  centre,  this  is  not  counteracted  by  the  con- 
traction of  the  arterioles  of  the  abdomen,  and  anaemia  of  the  brain  and 
syncope  are  liable  to  result.  The  operation  ought  not  to  be  commenced 
until  anaesthesia  is  complete  ;  otherwise  reflex  inhibition  of  the  heart  or 
shock  may  result  and  lead  to  fatal  results. 

Various  drugs  have  been  advised  as  preliminaries  to  anaesthesia, 
generally  with  the  object  of  preventing  the  reflex  arrest  of  the  respira- 
tion and  heart.  Thus  atropine  and  sparteine  have  been  proposed  to 
paralyze  the  vagus,  and  to  arrest  the  mucous  secretion  and  vomiting, 
and  spraying  of  the  nose  with  cocaine  has  recently  been  advised  to  par- 
alyze the  sensory  terminations  and  so  prevent  the  irritation  which  sets 
up  the  reflexes.  It  has  been  proposed  to  dilute  ether  or  chloroform 
vapor  with  oxygen  instead  of  air,  but  there  seems  no  theoretical  reason 
why  this  should  have  any  advantages,  and  in  practice  it  has  been  used 
in  too  limited  a  number  of  cases  to  allow  of  trustworthy  inferences. 
In  order  to  avoid  the  unpleasant  suffocating  effects  of  ether  and  to  per- 
mit of  less  concentrated  vapor  being  used,  the  injection  of  0.01-0.02  G. 
(i~i  gr-)  °f  morphine  has  been  advocated  as  a  preliminary  to  ether 
anaesthesia,  and  this  has  become  a  routine  procedure  in  some  clinics 
from  which  satisfactory  results  are  recorded.  In  others  some  less 
unpleasant  anaesthetic,  such  as  nitrous  oxide  or  ethyl  chloride,  is  used 
to  induce  anaesthesia,  which  is  afterwards  maintained  by  ether. 

Of  late  years  a  good  deal  of  interest  has  been  excited  by  the  dis- 
covery that  the  perils  of  anaesthesia  are  not  over  when  consciousness 
returns,  but  that  fatal  consequences  may  follow  several  days  later. 
These  late  fatalities  are  due  to  fatty  degeneration  of  the  heart  and 
kidneys  or  to  diabetic  coma  in  the  case  of  chloroform,  to  bronchitis, 
pulmonary  redema  and  pneumonia  after  ether.  No  reliable  data  are 
as  yet  available  as  to  the  frequency  of  these  sequelae,  as  it  is  very  diffi- 
cult to  distinguish  between  the  results  of  the  anaesthetic  and  the  ordi- 
nary forms  of  disease.  Even  the  proportion  of  cases  in  which  albumi- 
nuria  occurs  after  chloroform  seems  to  vary  remarkably  in  different 
hospitals,  for  it  is  given  as  low  as  5  per  cent,  by  some  authors  and  as 
high  as  30  per  cent,  by  others  ;  this  may  perhaps  be  explained  by  differ- 
ences in  the  duration  of  the  anaesthesia.  The  irritant  effects  of  ether  and 
the  liability  to  pulmonary  affections  afterwards  have  been  so  evident  that 
some  surgeons  have  returned  to  the  use  of  chloroform,  believing  that 
the  late  effects  in  ether  claimed  as  high  a  proportion  of  victims  as  the 
more  immediate  effects  of  chloroform.  Dreser  has  shown,  however, 
that  the  irritant  action  of  ether  and  its  consequent  dangers  may  be 
largely  avoided  by  the  use  of  dilute  vapor, 


176  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Therapeutic  Uses.  —  Anaesthesia  is  generally  induced  for  the  purpose 
of  surgical  operations  and  examinations,  and  in  labor.  Until  recent 
years,  when  it  was  necessary  to  perform  an  operation  or  manipulation 
involving  much  pain,  the  surgeon  had  to  consider  only  which  of  the 
two  general  anaesthetics  was  the  better  adapted  to  the  case.  But  the 
improvements  introduced  in  the  methods  of  inducing  local  anaesthesia 
and  the  reintroduction  of  nitrous  oxide  as  a  surgical  anaesthetic  have 
now  enlarged  his  field  of  choice,  and  the  further  question  has  to  be  met 
whether  unconsciousness  is  desirable,  or  whether  the  necessities  of  the 
case  may  not  be  met  by  paralyzing  sensation  at  the  seat  of  operation 
only.  The  advantages  claimed  for  local  anaesthesia  will  be  discussed 
under  cocaine,  but  the  general  conditions  in  which  chloroform  and 
ether  are  to  be  preferred  may  be  stated  shortly  (see  also  nitrous  oxide). 
General  anaesthesia  is  absolutely  essential  where  complete  relaxation  of 
the  muscles  is  desired,  and  where  the  movements  of  the  patient  may 
imperil  the  success  of  the  operation.  Operations  on  the  abdominal 
organs  and  around  joints  and  such  others  as  involve  wide  and  deep 
incisions  will  almost  certainly  continue  to  be  performed  under  chloro- 
form or  ether,  although  a  few  such  operations  have  been  attempted 
under  cocaine.  In  many  less  serious  operations  it  is  necessary  also  to 
have  recourse  to  the  older  methods,  which  allow  greater  freedom  to  the 
surgeon,  who  is  under  no  apprehension  that  he  may  reach  a  sensitive 
area  and  has  thus  one  less  source  of  anxiety  than  if  the  anaesthesia  were 
localized.  Another  argument  for  the  use  of  general  anaesthetics  is  the 
effect  which  the  anxiety  and  the  sights  and  sounds  of  the  operating 
room  may  have  on  a  nervous  patient  even  when  no  actual  pain  is  felt. 
And  a  considerable  amount  of  practice  is  required  before  complete  local 
anaesthesia  can  be  induced  over  an  extensive  field  of  operation,  while 
the  surgeon  has  often  to  interrupt  his  manipulations  in  order  to  admit 
of  a  fresh  area  being  rendered  analgesic.  But  there  is  no  question  that 
many  operations  in  which  ether  or  chloroform  has  hitherto  been 
employed,  will  in  the  future  be  performed  more  often  under  local  anaes- 
thesia or  nitrous  oxide.  In  this  class  may  be  included  most  minor 
operations  in  which  only  very  short  or  partial  anaesthesia  is  necessary 
and  in  which  no  complications  are  to  be  anticipated. 

During  labor  only  the  lighter  degrees  of  anaesthesia  are  necessary, 
the  object  being  to  dull  the  pain  without  lessening  to  any  marked 
extent  the  reflex  irritability  of  the  spinal  cord,  and  accidents  are 
extremely  rare  in  this  use  of  anaesthetics,  although  the  common  state- 
ment that  they  are  unknown  is  incorrect.  Some  cases  have  been 
recorded  in  which  it  is  believed  that  chloroform  was  fatal  to  the  child 
and  not  to  the  mother,  but  it  is,  of  course,  impossible  to  state  with  cer- 
tainty that  the  anaesthetic  was  the  cause  of  death.  If  too  deep  anaes- 
thesia is  produced,  however,  it  is  quite  conceivable  that  the  labor 
may  be  prolonged,  or  the  blood-pressure  so  reduced  as  to  lead  to 
an  imperfect  exchange  of  gases  in  the  placenta  and  thus  to  the 
death  of  the  infant ;  or  as  another  explanation  it  might  be  sug- 
gested that  the  irritability  of  the  respiratory  centre  of  the  child  may 


ETHER  AND   CHLOROFORM.  177 

be  so  reduced  that  it  fails  to  react  when  the  placental  circulation  is 
interrupted. 

Anaesthetics  are  also  employed  in  cases  of  extreme  irritability  of  the 
central  nervous  system,  as  in  strychnine  poisoning,  tetanus  or  other  con- 
vulsive affections.  In  order  to  reduce  these,  it  is  unnecessary  to  produce 
deep  anaesthesia,  a  few  whiffs  of  chloroform  being  generally  sufficient 
to  produce  quiet,  often  without  affecting  the  consciousness  to  any 
marked  extent.  In  cases  of  very  acute  pain,  chloroform  or  ether  may 
be  used,  but  as  a  general  rule  morphine  or  opium  is  preferable,  as  the 
action  lasts  much  longer  and  the  administration  is  much  more  con- 
venient. 

During  the  stage  of  excitement  of  anaesthesia,  the  dreams  of  the 
patient  sometimes  assume  an  erotic  character,  and  charges  of  criminal 
assault  have  been  repeatedly  brought  against  surgeons  by  women  whom 
they  had  anaesthetized.  It  is,  therefore,  advisable  to  give  chloroform 
to  women  only  in  the  presence  of  a  third  person. 

The  local  action  of  chloroform  and  ether  on  the  stomach  and  skin 
is  entirely  independent  of  the  action  as  anaesthetics,  and  has  to  be 
discussed  separately  (see  page  181). 

PREPARATIONS. 

U.  S.  P. — CHLOROFORMUM,  a  liquid  containing  99-99.4%  by  weight  of 
absolute  chloroform  (CHC13)  and  0.6-1%  of  alcohol. 

vETHER,  ether,  a  liquid  composed  of  about  96  %  by  weight  of  absolute  ether 
or  ethyl  oxide  ((C2H5)2O)  and  about  4%  of  alcohol  containing  a  little  water. 

^ETHYLIS  CHLORIDUM,  ethyl  chloride  (C2ELC1),  an  extremely  volatile  liquid 
boiling  at  12.5-13°  C.  (about  55°  F.). 

B.  P. — CHLOROFORMUM,  chloroform  (CHC13),  must  have  a  specific  gravity 
of  1.490-1.495,  that  is,  must  contain  99  per  cent,  of  absolute  chloroform. 

^Ether,  ether,  or  sulphuric  ether,  a  volatile  liquid  prepared  from  alcohol 
and  containing  not  less  than  92  fo  by  volume  of  pure  ether  or  ethyl  oxide 
((C2H5)20). 

JETHER  PURIFICATUS,  ether  freed  from  most  of  the  alcohol  or  water,  and 
of  0.720-0.722  specific  gravity. 

Chloroform  is  ordinarily  formed  by  the  action  of  chlorine  on  alcohol,  the 
chlorine  being  added  in  the  form  of  chlorinated  lime.  The  crude  drug  is 
purified  by  repeated  washing  with  water  and  sulphuric  acid,  and  dried  over 
calcium  chloride.  The  fatalities  following  its  use  have  frequently  been 
ascribed  to  impurities,  and  a  certain  demand  has  arisen  for  a  purer  article 
than  that  required  by  the  pharmacopoeias.  Another  method  of  preparation 
has  therefore  been  introduced,  the  decomposition  of  chloral  by  soda  (Chloro- 
formum  e  Chloral  pr separatum}.  Other  pure  forms  are  prepared  from  ordi- 
nary chloroform  by  crystallizing  it  by  cold  (Pictet),  or  by  forming  a  com- 
pound with  salicylid  and  decomposing  it  again  by  slight  heat,  Chloroform 
(Anschutz)  or  Chloroform  (Salicylid). 

The  impurities  of  chloroform  are  due  partly  to  imperfect  manufacture  and 
partly  to  decomposition.  Along  with  the  chloroform  there  distils  over  a 
small  quantity  of  heavy  oily  fluid,  which  may  be  isolated  by  Pictet' s  method, 
but  whose  composition  is  entirely  unknown.  DuBois-Reymond  found  that 
this  fluid  acted  more  strongly  on  the  heart  than  pure  chloroform,  but  it  is 
very  questionable  whether  the  minute  quantities  inhaled  in  ordinary  anaes- 
thesia produce  effects  of  any  importance,  and,  on  the  other  hand,  it  is  quite 
certain  that  the  use  of  absolutely  pure  chloroform  does  not  prevent  accidents. 
Chloroform  undergoes  decomposition  when  exposed  to  light  and  air,  hydro- 
12 


178  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

chloric  acid  and  chlorine  being  set  free  in  small  quantity.  These  can  affect 
the  course  of  anaesthesia  only  through  their  local  irritant  action,  but  if  pres- 
ent in  sufficient  quantity  may  cause  the  respiration  to  be  more  irregular  than 
usual  in  the  earlier  stages  ;  the  chloroform  used  for  anaesthetic  purposes 
ought,  therefore,  to  be  kept  in  a  dark  place  or  in  colored  bottles.  Another 
decomposition  occurs  when  chloroform  is  evaporated  in  the  neighborhood  of 
a  large  flame,  such  as  from  gas  or  lamps,  and  hydrochloric  acid  and  phosgen 
(CC12O)  are  formed,  the  latter  being  a  gas  with  exceedingly  irritant  prop- 
erties. 

Chloroform  is  a  heavy  volatile  fluid,  of  characteristic  pleasant  odor  and  hot 
sweetish  taste.  Its  specific  gravity  is  1.490  (U.  S.  P.)  and  1.490-1.495  (B.  P.), 
and  it  boils  at  60-62°  C.  A  number  of  tests  are  given  for  impurities,  but 
those  of  importance  can  generally  be  detected  by  the  odor,  especially  if 
some  chloroform  be  allowed  to  evaporate  in  a  watch-glass,  when  the  last 
drop  ought  to  have  no  irritant  effect  when  inhaled.  Chlorine  and  hydro- 
chloric acid  may  be  tested  for  by  shaking  the  chloroform  with  distilled  water, 
and  testing  the  latter  with  potassium  iodide  and  starch  and  with  silver  ni- 
trate. The  water  ought  to  give  no  acid  reaction  to  litmus.  If  left  in  contact 
with  concentrated  sulphuric  acid,  chloroform  should  not  become  darker  within 
one  hour,  as  this  indicates  the  presence  of  some  foreign  unstable  body. 
The  other  impurities  require  complicated  chemical  processes  for  their  detec- 
tion. 

Ether  is  prepared  by  the  action  of  sulphuric  acid  on  alcohol,  and  is  subse- 
quently purified  by  washing  with  water  and  alkalies.  It  seldom  contains 
impurities  of  importance.  2Ether  (B.  P.)  is  unsuited  for  anesthesia,  and,  in 
fact,  is  entirely  superfluous.  ^Ether  purificatus  (B.  P.)  and  ^Ether  (U.  S.  P.) 
are  practically  identical  and  are  the  forms  intended  for  inhalation.  Ether  is 
a  very  volatile  fluid,  of  a  suffocating,  irritant  odor  and  bitter  taste.  Its  specific 
gravity  is  0.725-0.728  (U.  S.  P.),  and  0.720-0.722  (B.  P.),  and  its  boiling  point 
is  36-37°  C.  It  evaporates  very  rapidly  in  the  air  and  should  leave  no  foreign 
odor  and  no  residue.  It  should  not  color  litmus  paper,  nor  be  colored  within 
an  hour  when  shaken  with  potassium  hydrate  solution.  Ether  vapor  is  exceed- 
ingly inflammable  when  mixed  with  air,  and  it  should  therefore  be  kept  in  a 
cool  place,  away  from  gas  flames  or  lamps. 

Various  other  members  of  the  fatty  series  have  been  introduced  as  general 
anaesthetics  at  different  times,  but  few  of  them  have  proved  to  have  any  advan- 
tage over  chloroform  and  ether,  and  fatalities  have  occurred  after  all  of  those 
that  have  received  a  wide  trial.  Pental,  trimethylethylene  ((CH3)2C  —  CHCH3) 
has  been  introduced  for  short  operations  within  the  last  few  years,  and  possesses 
the  advantage  that  no  after-effects  are  suffered  from,  the  patient  feeling  perfectly 
well  a  few  minutes  after  regaining  consciousness.  Its  use  is  not  absolutely  safe, 
however,  as  was  once  asserted,  for  several  accidents  have  occurred  under  it 
within  a  comparatively  short  time.  Pental  produces  anaesthesia  before  the 
reflexes  disappear  or  the  muscles  relax,  and  not  infrequently  the  jaws  are 
tightly  closed  after  consciousness  is  lost.  In  some  cases  tremor  and  convulsive 
attacks  have  occurred  during  its  administration,  but  it  seems  to  have  very  little 
action  on  the  heart  or  circulation.  In  the  frog  it  is  said  to  paralyze  the  ter- 
minations of  the  motor  nerves.  Ethyl  Bromide  (C2H5Br)  has  also  been  used 
largely  in  recent  years  for  short  operations  instead  of  chloroform,  and  pro- 
duces anaesthesia  with  great  rapidity.  Consciousness  returns  quickly  after 
the  removal  of  the  mask,  but,  on  the  other  hand,  the  inhalation  is  not  so 
pleasant  as  that  of  pental  and  patients  complain  of  greater  depression  and 
discomfort  afterwards.  Hennicke  found  that  10  vol.  per  cent,  of  ethyl  bro- 
mide were  necessary  to  anaesthetize  animals  within  5  minutes,  and  that  if 
this  concentration  were  maintained,  death  occurred  in  15  minutes,  so  that  it 
is  by  no  means  to  be  considered  a  perfectly  safe  anaesthetic  ;  several  deaths 
have  occurred  from  its  use  in  dentistry.  Both  pental  and  ethyl  bromide  are 
administered  on  a  mask  in  the  same  way  as  ether.  Ethyl  bromide  must  be 
distinguished  from  ethylene  bromide  (C2H4Br2)  which  is  a  much  more  dan- 


ETHER  AND   CHLOROFORM.  179 

gerous  anaesthetic.  Ethyl  bromide  is  very  liable  to  decomposition  when 
kept  long,  and  is  often  furnished  in  an  impure  form  ;  it  ought  to  be  perfectly 
colorless,  as  a  yellowish  color  indicates  decomposition,  often  with  the  pres- 
ence of  free  bromine.  Ethyl  Chloride  (C2H5C1),  or  Kelene,  has  been  advo- 
cated of  recent  years  as  an  anaesthetic  for  minor  operations  and  examinations 
and  appears  to  be  safer  and  more  satisfactory  than  the  bromide.  It  is  kept  in 
sealed  tubes  and  inhaled  through  a  mask  as  it  is  extremely  volatile,  boiling  at 
about  12°  0.  Anaesthesia  is  obtained  in  about  2-5  minutes,  but  complete  muscular 
relaxation  is  often  absent.  Recovery  follows  a  few  minutes  after  the  removal 
of  the  mask.  It  is  not  unpleasant  to  inhale  and  induces  no  unfavorable  symp- 
toms generally.  The  pulse  is  generally  slowed,  while  the  respiration  is  deep. 
The  blood-pressure  is  found  to  be  reduced  in  animals  in  deep  anaesthesia.  Some 
major  operations  have  been  performed  under  ethyl  chloride,  but  it  is  found  diffi- 
cult to  maintain  a  uniform  anaesthesia,  owing  to  the  rapidity  with  which  con- 
sciousness returns.  It  is  often  employed  to  introduce  anaesthesia,  which  is  then 
maintained  with  ether. 

The  other  members  of  this  series  possess  no  practical  importance.  It  may  be 
mentioned  that  tetrachloride  of  carbon  (CC14)  differs  from  the  others  in  causing 
convulsions,  while  perchlore thane  (C2C1?)  is  a  crystalline  solid  and  possesses  too 
high  a  boiling  point  to  be  available  for  inhalation. 

Various  Mixtures  of  the  Anaesthetics  have  been  advised  at  different 
times.  Of  these  the  ACE  mixture  (alcohol  1,  ether  2  and  chloroform  3  parts 
by  volume)  is  the  best  known.  Its  use  has,  however,  been  attended  with 
numerous  fatalities,  as  was  only  to  be  expected  from  a  consideration  of  the 
volatility  of  the  different  ingredients.  Ether,  being  the  most  volatile,  is  first 
inhaled,  and  then  chloroform,  and  last  of  all  the  alcohol.  The  safe  concen- 
tration of  ether  is,  however,  much  greater  than  that  of  chloroform,  and  a  vapor 
which  may  be  perfectly  safe  as  long  as  it  consists  of  ether  for  the  most  part, 
may  become  exceedingly  dangerous  when  it  consists  of  chloroform.  This 
method,  therefore,  increases  the  responsibility  of  the  chloroformist  by  leav- 
ing him  in  complete  ignorance  as  to  the  composition  of  the  anaesthetic  at 
any  given  time. 

A  new  series  of  mixtures,  advocated  recently  by  Schleich,  consists  of  dif- 
ferent proportions  of  chloroform,  ether,  and  petroleum  ether,  the  more 
volatile  part  of  petroleum  (boiling  at  60-65°  C.).  His  object  is  to  have  a 
fluid  which  boils  as  near  the  blood  temperature  (38.4°C.)  as  possible  but  it  is 
unnecessary  to  enter  into  the  theoretical  principles  on  which  he  based  his 
mixture  as  these  have  proved  to  be  erroneous  and  such  a  fluid  as  he  advises 
has  no  constant  boiling  point  (Braun).  The  anaesthesia  is  induced  and  main- 
tained for  the  most  part  by  the  ether,  which  forms  70-80  per  cent,  of  his  mix- 
ture, and  the  17^-24  per  cent,  of  chloroform  merely  accelerates  and  deepens  its 
action.  The  petroleum  ether  is  quite  superfluous,  and  the  danger  of  the  mix- 
ture lies  in  the  fact  that  the  vapor  consists  at  one  time  of  ether  mainly,  while 
later  most  of  it  may  be  chloroform.  In  favor  of  the  mixture  of  the  two  anaes- 
thetics it  has  been  urged  that  very  small  quantities  are  required  to  induce 
unconsciousness,  while,  on  the  other  hand,  the  respiration  is  more  unfavorably 
influenced  than  by  either  of  them  given  alone  (Honigmann).  Anesthol  is  a 
dangerous  mixture  of  ethyl  chloride,  chloroform  and  ether  ;  Somnoform,  of  ethyl 
chloride,  ethyl  bromide  and  methyl  chloride. 

Local  Action  and  Uses. 

In  addition  to  their  use  as  anaesthetics,  chloroform  and  ether  are 
sometimes  prescribed  for  the  same  purposes  as  the  volatile  oils. 
Chloroform  has  a  hot,  sweetish  taste,  while  ether  is  bitter  and  suffocat- 
ing in  the  mouth ;  a  sensation  of  heat  and  often  of  pain  in  the  stomach 
follows  when  they  are  swallowed,  and  chloroform  may  cause  gastric 
irritation  and  catarrh  when  given  undiluted.  The  movements  of  the 


180  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

stomach  are  accelerated,  and  Batelli  states  that  a  certain  amount  of 
shortening  of  the  muscular  fibres  occurs.  The  whole  effect  is  similar 
to  that  produced  by  the  volatile  oils,  but  absorption  probably  takes 
place  more  rapidly.  On  the  skin,  ether  evaporates  too  rapidly  to 
cause  much  irritation,  but  chloroform  is  occasionally  used  as  a  rube- 
facieut  in  the  form  of  a  liniment. 

PREPARATIONS. 

The  pure  substances  may  be  administered  by  the  mouth,  but  more  fre- 
quently other  preparations  are  prescribed. 

Chloroform,  0.5-1  c.c.  (8-15  mins.). 

uEther,  0.5-1  c.c.  (8-15  mins.). 

SPIRITUS  JETHERIS  (U.  S.  P.,  B.  P.),  2-5  c.c.  (30-90  m.). 

SPIRITUS  ^ETHERIS  COMPOSITUS  (U.  S.  P.,  B.  P.)  (Hoffmann's  Anodyne) 
contains  a  number  of  esters  of  ethyl  and  other  substances  known  as 
"  ethereal  oil,"  together  with  ether  and  alcohol,  2-4  c.c.  (|-1  fl.  dr.). 

SPIRITUS  CHLOROFORMI  (U.  S.  P.,  B.  P.),  1-4  c.c.  (20-60  min.)  (5-20  m. 
for  repeated  doses,  B.  P.). 

Emulsum  Chloroformi  (U.  S.  P.),  15-30  c.c.  (£-1  fl.  oz.). 

Aqua  Chloroformi  (U.  S.  P.,  B.  P.). 

Liniment  urn  Chloroformi  (U.  S.  P.,  B.  P.). 

Tinctura  Chloroformi  et  Morphinse  Composita  (B.  P.)  contains  one  per  cent,  of 
morphine  hydrochlorate,  chloroform,  prussic  acid,  cannabis  indica,  capsicum 
and  oil  of  peppermint,  and  represents  the  patented  medicine  "  chlorodyne." 
Dose,  5-15  m.  It  is  used  as  a  soporific  (see  morphine). 

yEther  Aceticus  (U.  S.  P.,  B.  P.),  acetic  ether,  an  ethereal  fluid  consisting 
of  ethyl  acetate,  1-3  c.c.  (20-40  mins.). 

Therapeutic  Uses.  —  These  preparations  are  used  for  the  same  pur- 
poses as  the  corresponding  preparations  of  the  volatile  oils.  Thus  the 
spirits  and  emulsion  may  be  prescribed  as  carminatives  or  in  colic, 
while  the  liniment  is  used  as  a  counter-irritant.  Chloroform  water  is 
an  antiseptic  of  considerable  power,  but  is  too  volatile  for  surgical  use. 

Spirits  of  ether  and  ether  itself  are  often  given  internally  or  sub- 
cutaneously  in  cases  of  shock  or  sudden  collapse  in  the  same  way  as 
brandy  or  whiskey,  though  Elfstrand  states  that  ether  injected  hypo- 
dermically  has  no  effect  on  the  heart  or  blood-pressure ;  spirits  of 
ether  contains  a  much  larger  percentage  of  alcohol  than  ordinary 
whiskey.  Both  ether  and  chloroform,  but  more  especially  the  latter, 
have  been  used  internally  for  tapeworm  with  success.  There  is  always 
some  danger,  however,  that,  besides  destroying  the  parasite,  they  may 
cause  irritation  and  lasting  injury  to  the  intestinal  wall. 

Hofmann's  anodyne  is  a  favorite  carminative,  and  is  often  added  to 
other  drugs  to  lend  them  an  agreeable  odor  and  taste.  It  is  also  used 
in  dilution  as  a  stimulant  in  the  same  indefinite  way  as  wine  and 
spirits,  and  its  large  percentage  of  alcohol,  together  with  the  bouquet 
given  it  by  the  various  esters  present,  entitle  it  to  be  ranked  among 
the  alcoholic  preparations. 

Both  spirits  of  ether  are  used  occasionally  in  expectorant  mixtures 
and  are  believed  to  increase  the  bronchial  secretion. 

Ether  evaporates  very  rapidly  and  leaves  a  sensation  of  cold,  and 
when  thrown  on  the  skin  in  a  fine  spray  it  produces  sufficient  cold 


ETHER  AND   CHLOROFORM.  181 

to  numb  sensation  in  the  part  and  allow  of  minor  surgical  operations. 
(See  uses  of  cocaine.)  Instead  of  ether  still  more  volatile  substances, 
such  as  ethyl  chloride  (boiling  point  12.5°  C.)  and  methyl  chloride 
(boiling  point  —  23°  C.)  have  been  introduced.  The  latter  is  supplied 
in  pressure  cylinders,  and  is  allowed  to  escape  against  the  skin,  while 
the  others  are  thrown  against  it  by  pumping  air  through  them.  The 
local  anaesthesia  produced  bears  no  relation  to  their  action  when 
inhaled,  but  is  due  simply  to  the  cold  produced  by  their  evapora- 
tion. The  vessels  of  the  part  contract,  and  the  absence  of  blood  and 
hardness  of  the  tissues  facilitate  some  operations,  but  the  subsequent 
reaction  is  liable  to  produce  considerable  soakage  of  blood  from  the 
wound.  The  cold  elicited  ought  not  to  be  great  enough  to  actually 
freeze  the  tissues,  otherwise  the  healing  may  be  slow.  The  intense 
cold  is  often  quite  as  painful  as  the  operation  itself  would  be  without 
any  anaesthetic. 

BIBLIOGRAPHY  OF  ETHER    AND  CHLOROFORM. 

The  literature  up  to  1880  is  given  in  Kappeler's  "  Ansesthetica,"  Stuttgart,  1880. 

Dastre.     Les  Ansesthesiques,  Paris,  1890. 

Report  of  the  Hyderabad  Chloroform  Commission,  Bombay,  1891,  and  Lancet,  1890. 
The  criticisms  on  the  report  are  dealt  with  in  the  Lancet,  1890- -91,  and  in  the  British 
Medical  Journal,  1890-91. 

Mac  William.     Proc.  Koy.  Soc.,  liii.,  p.  464;  Journ.  of  Physiol.,  xxv.,  p.  235. 

Cook  and  Briggs.     Johns  Hopkins  Hospital  Report,  xi.,  p.  451. 

Blauel.     Beitrago  z.  klin.  Chir.,  xxxi.,  p.  271. 

Embley.     Brit.  Med.  Journ.,  April,  1902. 

Moore  and  Roaf.     Proc.  Roy.  Soc.,  Ixxiii.,  p.  382. 

Sherrington  and  Sowton,  Waller,  Horsley,  and  others.  Brit.  Med.  Journ.,  July  12, 
1902;  July  18,  1903;  July  23,  1904;  Sept.  24,  1904. 

Loeb.     Arch.  f.  exp.  Path.  u.  Pharm.,  li.,  p.  82. 

Schafer  and  Scharlieb.     Trans.  Roy.  Soc.  Edinb.,  xli.  (ii.),  p.  311. 

Hill     Brit.  Med.  Journ.,  1897,  April. 

Dieballa.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv.,  p.  137. 

Hogyes.     Ibid.,  xvi!,  p.  81. 

Pohl.     Ibid.,  xxviii.,  p.  239. 

Limbourg.     Ibid.,  xxx.,  p.  93. 

Nauwerck.     Deutsche  med.  Woch.,  1895,  p.  121. 

Poppert.     Ibid.,  1894,  p.  719. 

Miculicz.     Berlin,  klin.  Woch.,  1894,  p.  1035. 

Bruns.     Ibid.,  p.  1147. 

SalkowsH.     Zts.  f.  klin.  Med.  (Suppl.),  xvii.,  p.  77. 

Ungar.     Vierteljahr.  f.  ger.  Med.,  xlvii.,  p.  98. 

Mertens.     Arch,  de  Pharmacodynam.,  ii.,  p.  127. 

Kasl  u.  Mester.  Zts.  f.  klin.  Med.,  xviii.,  p.  469 ;  Zts.  f.  phys.  Chem.,  xiv  p.  277 ; 
xii.,  p.  267. 

Savelie/.     Virchow's  Arch.,  cxxxvi.,  p.  195. 

Ambrosius.     Ibid.,  cxxxviii.,  Suppl.,  p.  193. 

Lippmann.     Mittheil.  a.  d.  Grenzgebiet  der  Med.  u.  Chir.,  iv.,  p.  21. 

Selbach.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv.,  p.  1. 

Becker.     Virchow's  Arch.,  cxl.,  p.  1. 

Spenzer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiii.,  p.  407. 

Rosenfeld.     Ibid.,  xxxvii.,  p.  52. 

Dreser.  Beitriige  zur  klin.  Chirurg.,  x.,  p.  412,  and  xii.,  p.  353.  Arch.  f.  exp. 
Path.  u.  Pharm.,  xxxvii.,  p.  375.  Bulletin  of  Johns  Hopkins  Hospital,  vi.,  p.  7, 1895. 

Hennicke.     Inaug.  Diss.  Bonn.,  1895. 

Heymannset  Debuck.     Arch,  de  Pharmacodyn. ,  i.,  p.  1. 

R.  du  Bois-Reymond.     Therap.  Monatsch.,  1892,  p.  21. 

Paton.     Phil.  Trans.  Roy.  Soc.,  1894,  p.  251. 

Lambert  et  Gamier.     Jour,  de  Phys.,  ii.,  p.  902. 


182  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Pereles  u.  Sachs.     Pfliiger's  Arch.,  lii.,  p.  526. 
Kemp.     New  York  Med.  Journ.,  1899,  ii.,  p.  732. 
Thompson,  Buxton,  Levy.     Brit.  Med.  Journ. ,  1900,  ii.,  p.  833. 
Duplay  et  Hallion.   Arch.  gen.  de  Med.,  clxxxvi.,  p.  129. 

Da  Costa.     American  Medicine,  1901,  May  18th.     Annals  of  Surgery,  1901,  Sept. 
Sjiel.     Berlin,  klin.  Woch.,  1903,  p.  212. 
Braun.     Arch.  f.  klin.  Chirurg.,  Ixiv.,  p.  201. 
Honigmann.     Arch.  f.  klin.  Chirurg.,  Iviii.,  p.  730. 
Kionka.     Ibid.,  1.,  p.  339. 

Pick.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlii.,  p.  412. 
Elf  strand.     Ibid.,  xliii.,  p.  435. 

Sackur.     Virchow's  Arch.,  cxxxiii.,  p.  30.     (Pental.) 
Zoepfel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlix.,  p.  89.     (Ethyl  chloride.) 
Seherbatscheff.     Ibid.,  xlvii.,  p.  1.     (Ethyl  bromide.) 
Cole.     Brit.  Med.  Journ.,  June  20,  1903.     (Ethyl  bromide.) 
McCordie.     Lancet,  April  4th,  1903.      (Ethyl  chloride.) 
Hewitt.     Ibid.,  Nov.  19,  1904.     (Ethyl  chloride.) 

Montgomery  and  Bland.  Journ.  of  Amer.  Med.  Assoc.,  April  2,  1904.  (Ethyl 
chloride. ) 

3.    Nitrous  Oxide. 

The  oldest  of  the  anaesthetics,  nitrous  oxide,  N2O,  does  not  belong 
to  the  methane  series,  but  may  be  discussed  at  this  point. 

Symptoms.  —  When  a  mixture  of  nitrous  oxide  and  air  is  inhaled 
for  a  few  seconds,  a  condition  resembling  alcoholic  intoxication  is 
produced,  with  much  hilarity  and  laughter,  so  that  the  oxide  is 
known  popularly  as  "laughing  gas."  Even  at  this  point  a  certain 
amount  of  anaesthesia  is  obtained,  and  it  was  the  observation  that  persons 
falling  during  this  stage  did  not  complain  of  pain  that  first  suggested  to 
Wells  the  anaesthetic  properties  of  the  gas.  Davy  had  noted  these 
forty  years  previously,  but  his  suggestion  that  nitrous  oxide  might  be 
used  in  surgical  operations  passed  unnoticed. 

The  inhalation  of  a  mixture  of  nitrous  oxide,  4  parts,  and  oxygen, 
1  part,  causes  after  a  few  seconds  a  rushing,  drumming,  hammer- 
ing in  the  ears,  indistinct  sight,  and  a  feeling  of  » warmth  and  com- 
fort. The  movements  become  exaggerated  and  uncertain,  the  gait  is 
staggering,  and  the  body  sways  from  side  to  side.  The  patient  seems 
brighter  and  more  lively,  and  often  bursts  into  laughter.  Somewhat 
later  a  feeling  of  drowsiness  may  come  on,  but  this  is  not  constant ; 
the  sensibility  to  pain  is  much  less  acute  than  normally,  but  no  com- 
plete anaesthesia  is  produced  by  this  mixture  of  gases ;  the  sense  of 
touch  is  comparatively  little  altered,  and  total  unconsciousness  never 
results.  The  pupil  is  generally  slightly  dilated,  the  face  flushed,  and 
the  pulse  somewhat  accelerated. 

When  pure  nitrous  oxide  is  inhaled  without  the  admixture  of  oxy- 
gen, the  patient  passes  almost  instantaneously  through  the  symptoms 
already  described,  but  then  loses  consciousness  completely ;  the  face  is 
cyanotic,  the  respiration  becomes  stertorous  and  dyspnoeic  and  ceases 
after  a  weak  convulsion,  while  the  heart  continues  to  beat  for  some 
time  afterwards.  If  the  mask  through  which  the  patient  has  been 
inhaling  the  gas  be  removed  when  the  cyanosis  becomes  marked,  very 
complete  anaesthesia  lasts  for  30-60  seconds,  and  the  patient  then 
recovers  within  a  few  minutes  and  suffers  from  no  after-effects  what- 
ever. No  prolonged  anaesthesia  can  be  produced,  however,  as  the  res- 


OXIDE. 

piration  becomes  endangered  if  the  mask  be  kept  on  longer  than  the 
beginning  of  the  cyanotic  stage. 

Action.  —  Nitrous  oxide  supports  combustion  outside  the  body,  for  if 
a  glowing  splinter  of  wood  be  held  in  it,  it  bursts  into  flame  exactly 
as  if  it  were  immersed  in  oxygen.  It  was  accordingly  believed  at  one 
time  that  nitrous  oxide  supported  the  combustion  of  the  living  tissues 
in  the  same  way  as  oxygen,  but  this  has  been  disproved,  for  as  far  as 
the  metabolism  of  protoplasm  is  concerned,  nitrous  oxide  behaves  in  the 
same  way  as  any  other  indifferent  gas,  such  as  hydrogen  or  nitrogen  ; 
that  is,  the  tissues  exposed  to  it  suffer  from  asphyxia  owing  to  the  oxygen 
of  the  air  being  excluded.  Thus,  plants  do  not  grow  in  an  atmosphere 
of  nitrous  oxide  and  seeds  do  not  germinate.  Animals  die  after  in- 
haling nitrous  oxide  in  almost  the  same  time  as  after  hydrogen  or 
nitrogen,  and  at  death  the  spectrum  of  the  blood  shows  no  oxyhsemo- 
globin  to  be  present,  the  tissues  having  used  up  all  the  available 
oxygen.  Nitrous  oxide,  therefore,  does  not  support  combustion  in  the 
animal  body,  the  nitrogen  is  not  split  off  from  the  oxygen  as  it  is  when 
the  oxide  is  exposed  to  high  temperatures  outside  the  body. 

Another  question  is  whether  nitrous  oxide  behaves  only  as  an  in- 
different gas  in  the  body,  or  whether  it  has  not  some  special  effect  on 
the  central  nervous  system,  although  in  the  rest  of  the  tissues  it  acts 
only  by  excluding  the  oxygen.  The  earlier  workers  in  this  field  held 
that  it  affected  the  central  nervous  system  only  by  cutting  off  its  sup- 
ply of  oxygen,  but  this  has  been  shown  to  be  erroneous,  for  nitrous 
oxide  acts  as  a  depressant  to  the  central  nervous  system  by  virtue  of  its 
molecular  form  just  as  chloroform  or  ether  does.  This  has  been  shown 
in  a  variety  of  ways  ;  thus,  if  it  were  a  perfectly  indifferent  body  no 
more  effect  would  be  produced  by  it  when  mixed  with  one  fourth  of  its 
volume  of  oxygen  than  by  air,  which  consists  of  1  part  of  oxygen 
and  4  parts  of  an  indifferent  gas,  nitrogen.  But  80  per  cent,  nitrous 
oxide  has  definite  effects  on  the  behavior  of  animals,  as  has  been  men- 
tioned, and  even  73  per  cent,  produces  some  slowing  of  the  respira- 
tion. The  narcotic  action  was  demonstrated  very  clearly  by  Paul  Bert 
in  a  series  of  experiments  on  man  and  animals.  He  noted  that  only 
imperfect  anaesthesia  was  produced  by  80  per  cent,  nitrous  oxide,  while 
the  pure  gas  produced  asphyxia.  The  problem  was  to  introduce  as 
much  gas  into  the  blood  as  would  pass  in  under  pure  nitrous  oxide, 
and  at  the  same  time  to  supply  sufficient  oxygen  to  prevent  asphyxia. 
The  absorption  of  nitrous  oxide  depends  upon  its  partial  pressure  in 
the  lungs,  as  it  is  simply  dissolved  in  the  blood  without  forming  any 
real  combination  with  it,  and  the  quantity  absorbed  by  the  blood  may 
be  augmented  by  increasing  the  barometric  pressure.  Bert,  therefore, 
administered  a  mixture  of  80  parts  nitrous  oxide  and  20  parts  oxygen 
to  animals  in  a  glass  case  in  which  the  pressure  was  raised  one  fourth 
above  the  ordinary  atmospheric  pressure.  The  absorption  of  the 
nitrous  oxide  was  the  same  as  if  the  animal  had  breathed  the  pure  gas 
at  the  ordinary  air  pressure,  and  at  the  same  time  as  much  oxygen  was 
absorbed  as  in  ordinary  air.  The  result  was  a  complete  anesthesia 


184  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

without  asphyxia,  which  could  be  maintained  for  3  days  without  in- 
jury to  the  animal  (Martin).  Kemp  has  recently  shown  that  mix- 
tures of  oxygen  and  nitrous  oxide  can  be  inhaled  for  some  time  and 
produce  anaesthesia,  which  passes  off  at  once  when  nitrogen  is  substi- 
tuted for  nitrous  oxide.  He  has  further  investigated  the  blood  gases 
during  nitrous  oxide  anaesthesia,  and  finds  that  the  oxygen  contained 
in  the  blood  at  the  deepest  stage  of  anaesthesia  is  quite  sufficient  to 
maintain  life  and  consciousness  were  no  nitrous  oxide  present.  Again 
Goltstein  found  that  frogs  were  narcotized  in  5J  minutes  in  an  atmos- 
phere of  nitrous  oxide,  in  1 J  hours  in  hydrogen,  and  showed  that  the 
narcosis  and  death  in  mammals  from  nitrous  oxide  differed  in  several 
details  from  that  under  indifferent  gases.  There  can,  therefore,  be  no 
doubt  that  nitrous  oxide  has  distinct  effects  on  the  central  nervous 
system,  although  it  is  indifferent  to  the  other  tissues.  A  further  ques- 
tion arises,  whether  the  anaesthesia  produced  by  it  in  ordinary  use  is 
due  to  this  specific  action  on  the  nerve  cells  alone  or  to  the  asphyxia. 
Wood  has  shown  that  even  a  slight  admixture  of  oxygen  (3  per  cent.) 
delays  anaesthesia  considerably,  so  that  the  lack  of  oxygen  appears  to 
aid  the  direct  effects  of  the  anaesthetic.  Bert's  and  Martin's  experi- 
ments would  indicate  that  death  occurs  not  from  the  direct  action  of  the 
nitrous  oxide  on  the  respiratory  centre,  but  from  the  lack  of  oxygen,  al- 
though the  depression  of  the  centre  is  undoubtedly  a  contributing  factor. 

The  same  question  arises  regarding  the  action  on  the  nerve  cells  as 
has  been  met  with  in  the  members  of  the  methane  series,  and  here 
again  the  preliminary  excitement  would  seem  to  indicate  not  stimu- 
lation of  the  brain  areas,  but  lessened  activity  of  the  functions  of 
control  and  restraint. 

The  respiratory  centre  is  depressed  when  the  gas  is  inhaled  in  com- 
paratively dilute  form,  for  Zuntz  and  Goltstein  found  the  breathing 
slower  and  deeper  after  73  per  cent.  The  respiration  ceases  some- 
what earlier  under  nitrous  oxide  than  under  indifferent  gases,  which 
would  indicate  that  the  cessation  of  the  breathing  is  due  at  any  rate 
in  part  to  the  specific  depressant  action.  In  asphyxia  from  nitrous 
oxide  there  is  less  convulsive  movement  than  under  hydrogen,  owing 
to  the  general  depression  of  the  nerve  cells. 

The  circulation  is  little  affected  by  the  nitrous  oxide  directly,  the  rise 
in  the  blood-pressure  and  slowness  of  the  pulse  being  due  to  the 
asphyxial  condition  of  the  blood  ;  the  pulse  is  not  so  slow  as  in  ordinary 
asphyxia  or  in  asphyxia  from  nitrogen  or  hydrogen,  because  the  in- 
hibitory centre  is  less  capable  of  activity.  The  heart  is  not  affected 
directly,  but  only  by  the  lack  of  oxygen. 

Nitrous  oxide  is  dissolved  in  the  blood  exactly  as  in  water.  There 
is  no  combination  formed  with  any  of  the  constituents,  nor  is  the 
haemoglobin  altered  in  any  respect. 

Nitrous  oxide  is  a  gas  at  ordinary  temperature  and  pressure,  and  is 
invariably  administered  by  inhalation  from  a  cylinder  into  which  it 
has  been  forced  under  high  pressure.  The  mask  generally  covers  both 
nose  and  mouth,  and  the  inhalation  is  carried  on  until  distinct  cyano- 


NITEOUS  OXIDE.  185 

sis  appears,  when  the  anaesthesia  is  sufficient  to  allow  of  short  oper- 
ations, such  as  those  of  dentistry.     It  is  much  the  safest  of  the  anaes- 
thetics, for  millions  of  persons  have  been  subjected  to  its  influence, 
and  as  yet  only  ten  cases  of  death  are  reported  from  its  use,  and  sev- 
eral of  these  do  not  seem  to  have  been  due  to  the  direct  action  of  the 
gas.     Unfortunately,  the  anaesthesia  cannot  be  kept  up  except  for  a 
very  short  time,  which  is  quite  insufficient  to  allow  of  ordinary  oper- 
ative procedures.     A  number  of  attempts  have  been  made  to  prolong 
the  anaesthesia,  of  which  Bert's  was  much  the  most  successful.     The 
operator,  patient  and  attendants  were  enclosed  in  an  air-tight  chamber, 
the  air  pressure  was  raised  by  means  of  force  pumps,  and  Bert's  mixture 
of  oxygen  and  nitrous  oxide  was  inhaled  by  the  patient.    A  whole  series 
of  major  operations  were  performed  in  this  way,  the  anaesthesia  being 
complete  as  long  as  was  desired,  and  the  patient  recovering  a  few 
minutes  after   the  mask  was  removed.     The  only  objections  to  the 
method  were  the  great  expense  of  the  chamber  and  of  pumping  the 
air,  and  the  inconvenience  attending  the  whole  procedure.     Bert,  there- 
fore, proposed  later  to  induce  anaesthesia  by  pure  nitrous  oxide,  and 
then  to  substitute  for  it  a  mixture  of  oxygen  and  nitrous  oxide,  and  to 
keep  up  the  anaesthesia  as  long  as  desired  by  alternating  between  the 
pure  gas  and  the  mixture.     A  practical  method  of  carrying  out  this 
form  of  anaesthesia  has  been  devised  by  Hewitt,  whose  results  have 
led  to  a  wider  trial  of  diluted  nitrous  oxide  anaesthesia  than  it  has 
hitherto  had.     His  apparatus  consists  essentially  of  two  reservoirs,  the 
one  containing  oxygen,  the  other  nitrous  oxide,  and  of  a  mixing  cham- 
ber with  a  stopcock  by  which  the  proportion  of  oxygen  is  regulated. 
A  tube  leads  from  the  mixing  chamber  to  the  mask  which  must  fit 
closely  to  the  face.     The  inhalation  is  commenced  with  pure  nitrous 
oxide  or  with  a  mixture  containing  only  2  per  cent,  of  oxygen.     When 
anaesthesia  is  attained  the  percentage  of  oxygen  is  increased  to  5-8  per 
cent,  by  turning  the  stopcock,  and  the  symptoms  determine  the  further 
changes,  returning    consciousness    necessitating  a  diminution    in   the 
oxygen,  stertor  and  cyanosis  an  increase.     This  form  of  anaesthesia  is 
admirably  adapted  for  minor  operations  and  has  been  maintained  in 
some  cases  for  as  long  as  an  hour.     The  circulation  and  respiration 
are  less  seriously  altered    than   by  any  other  method    that  induces 
general  anaesthesia,  and  the  return  of  consciousness  is  almost  immediate. 
The  great  drawback  to  its  use  is  the  cumbrous  apparatus  required  and 
the  large  amount  of  gas  used,  amounting  to  about  100  gallons  for 
anaesthesia  of  half  an  hour.     Complete  muscular  relaxation  is  seldom 
attained  and  this  precludes  its  use  in  many  operations,  in  which  how- 
ever it  may  be  employed  at  first  and  then  be  replaced  by  chloroform 
or  ether,   whose  preliminary  disagreeable    effects  are  thus   avoided. 
Klikowitsch  proposed  the  use  of  80  per  cent,  nitrous  oxide,  not  for 
complete  anaesthesia,  but  to  relieve  pain  and  spasm  in  cases  of  asthma, 
in  labor  and  similar  conditions.     The  patient  could  inhale  it  if  neces- 
sary without  the  presence  of  a  medical  attendant,  and  it  had  the  ad- 


186  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

vantage  over  the  other  depressants  that  it  need  only  be  inhaled  when  an 
attack  of  pain  was  approaching  and  that  it  left  no  depression  afterwards. 

The  high  blood-pressure  induced  by  nitrous  oxide  asphyxia  is  some- 
times said  to  be  dangerous  in  elderly  persons  from  their  liability  to 
apoplexy,  and  of  the  few  fatalities  under  the  gas  several  would  seem 
due  rather  to  this  than  to  the  drug  directly,  but  the  danger  is  often 
overstated,  and,  in  fact,  it  is  a  question  whether  the  shock  caused  by  the 
operation  without  gas  would  not  be  more  dangerous  than  the  effects  of 
the  gas  itself.  No  such  symptoms  arise  when  the  nitrous  oxide  is 
diluted  with  oxygen  as  in  Hewitt's  method. 

Occasionally  some  glycosuria  occurs  after  the  inhalation,  not  owing 
to  the  gas  itself,  but  to  the  accompanying  asphyxia.  It  is  merely  tem- 
porary and  has  no  practical  importance. 

The  treatment  of  accidents  in  anaesthesia  under  nitrous  oxide  con- 
sists in  artificial  respiration  alone. 

BIBLIOGRAPHY. 


Paul  Bert.     Comptes  rendus,  Ixxxvii.,  p.  728,  and  xcvi.,  p.  1271. 
Hermann.     Arch.  f.  Anat.  und  Phys.,  1864,  p.  521. 
Jolyet  et  Blanche.     Arch,  de  Phys.,  1873,  p.  364. 


Goltstein.     Pfl tiger's  Arch.,  xvii.,  p.  331. 

Klikoivitsch.     Virchow's  Arch.,  xciv.,  p.  148.     (Literature.) 

Martin.     Comptes  rendus,  cvi.,  p.  290. 

Van  Arsdale.     Am.  Journ.  Med.  Sciences,  cii.,  p.  131. 

Wood.     Dental  Cosmos,  1893. 

Kemp.     Brit.  Med.  Journ.,  1897,  ii.,  p.  1480. 

Hewitt.     Anaesthetics  and  their  administration,  London,  1900. 

V 

4.   Soporifics. — Chloral. 

Some  twenty  years  after  the  introduction  of  the  anaesthetics,  a  new 
interest  was  given  to  the  methane  series  by  the  examination  of  the  ac- 
tion of  chloral  by  Liebreich.  Henceforth  the  attention  of  investigators 
was  diverted  from  the  quest  of  anaesthetics  to  that  of  hypnotics,  with 
the  result  that  a  very  large  number  of  bodies  have  since  been  suggested 
for  this  purpose  and  that  a  few  valuable  drugs  have  been  added  to 
therapeutics.  These  soporifics,  or  narcotics,  have  the  same  general 
action  as  the  anaesthetics,  but  are  used  only  to  produce  the  first  effects 
of  imperfect  consciousness  or  sleep.  The  anaesthetics  might  be  used 
for  this  purpose  were  it  not  for  the  comparatively  short  time  during 
which  their  action  persists.  Narcotics  are  required  to  produce  a  slight 
but  lasting  effect,  and  for  this  purpose  the  gradual  absorption  from  the 
stomach  is  better  adapted  than  the  rapid  absorption  and  equally  rapid 
elimination  by  the  lungs.  The  narcotics  are,  therefore,  less  volatile 
than  the  anaesthetics,  and  ought  to  be  soluble  in  water  and  not  irritant 
in  the  stomach,  so  as  to  permit  of  rapid  absorption.  Chloral  is  still 
the  best  known  and  most  widely  used  member  of  this  group. 

Symptoms,  —  In  small  quantities  chloral  produces  drowsiness  and 
weariness,  which  soon  pass  into  a  condition  resembling  natural  sleep 
very  closely,  from  which  the  patient  can  be  awakened  by  ordinary  means, 


SOPORIFICS- CHLORAL.  187 

such  as  touching,  loud  sounds,  or  pain.  The  respiration  and  pulse 
are  somewhat  slower  than  in  waking  moments,  but  scarcely  more  so 
than  in  natural  sleep,  and  the  somewhat  narrowed  pupil  and  unaltered 
excitability  of  the  reflexes  are  also  common  to  both  conditions.  As  a 
general  rule,  the  sleep  passes  off  in  5—8  hours  and  leaves  no  unpleasant 
results,  but  sometimes  headache,  giddiness  and  confusion  are  com- 
plained of.  Occasionally  no  real  sleep  is  produced  by  chloral,  a 
condition  exactly  resembling  alcoholic  intoxication  following  its  ad- 
ministration and  continuing  for  some  time.  When  larger  quantities, 
e.  g.j  5  G.  (75  grs.),  are  taken,  the  sleep  is  much  deeper,  the  patient 
cannot  be  aroused  to  complete  consciousness,  the  reflexes  are  distinctly 
lessened  and  the  sensation  of  pain  is  less  acute,  although  no  complete 
anaesthesia  is  present.  The  respirations  are  fewer  and  the  pulse  may 
be  slow  and  somewhat  weak.  The  sleep  lasts  very  much  longer  (10— 
15  hours),  and  nausea,  vomiting,  headache  and  confusion  often  remain 
after  consciousness  is  regained.  In  still  larger  quantities  chloral  pro- 
duces a  condition  resembling  exactly  the  third  stage  of  anesthesia. 
The  reflexes  are  entirely  absent  and  no  movement  is  elicited  by  pain- 
ful operations,  the  muscles  are  completely  relaxed,  the  respiration  and 
pulse  are  both  slow  and  weak,  and  eventually  asphyxia  occurs  from 
paralysis  of  the  respiratory  centre.  The  heart  continues  to  beat  for  a 
short  time  after  the  breathing  ceases. 

The  first  stage  is  the  only  one  elicited  in  therapeutics.  The  use  of 
chloral  as  an  anaesthetic  would  be  quite  unjustifiable,  because  it  is  im- 
possible to  adjust  the  dose  accurately  enough  to  allow  of  complete 
anaesthesia  without  danger  of  respiratory  failure. 

Action.  —  The  Central  Nervous  System  is  depressed  and  eventually 
completely  paralyzed  by  chloral  and  its  allies.  Unlike  the  anaesthetics 
and  alcohol,  however,  chloral  rarely  causes  excitement,  but  this  may 
be  due  to  the  facts  that  the  surroundings  of  the  patient  are  less  likely 
to  cause  excitement  and  that  the  drug  itself  causes  less  local  irritation. 
The  results  of  psychological  experiments  on  the  effects  of  small  doses 
of  the  narcotics  seem  to  indicate  that  they  all  depress  the  sensory  or  re- 
ceptive functions  of  the  brain,  while  its  motor  activity  is  much  reduced 
by  chloral  and  sulphonal,  but  may  appear  to  be  actually  increased  by 
paraldehyde ;  this  apparent  stimulation  is  analogous  to  that  under 
alcohol  and  may  be  explained  by  lessened  control.  The  sleep  induced 
by  the  dulling  of  the  perceptions  may  be  interrupted  by  more  intense 
stimuli  from  without.  In  particular,  acute  pain  may  prevent  sleep 
after  chloral,  which  seems  to  have  no  specific  effects  on  the  algesic 
areas,  such  as  is  possessed  by  morphine ;  the  sensibility  of  the  skin  is 
also  less  affected  by  chloral  than  by  morphine.  In  larger  quantities, 
however,  even  very  great  disturbance  of  the  environment  produces  no 
interruption  of  the  sleep,  and  the  reflex  response  to  irritation  is 
very  much  lowered.  The  motor  areas  of  the  brain  cortex  are  rendered 
less  irritable  by  chloral,  and  eventually  fail  to  react  to  the  strongest 
electrical  stimulation.  The  reflexes  of  the  spinal  cord  are  depressed 


188  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

and  finally  paralyzed  before  the  failure  of  the  respiration.1  The 
depression  of  the  reflexes  is  one  of  the  points  which  serve  to  differenti- 
ate the  action  of  most  of  the  methane  series  from  that  of  the  alkaloidal 
narcotics,  such  as  morphine.  The  last  part  of  the  central  nervous  sys- 
tem to  be  attacked  is  the  medulla  oblongata,  for  although  the  respira- 
tion is  somewhat  slower  and  shallower  after  small  quantities,  it  is 
scarcely  more  affected  than  in  ordinary  sleep,  and  Loewy  found  that 
both  the  excitability  of  the  centre  and  the  volume  of  the  inspired  air 
were  very  similar  in  the  two  conditions.  As  the  dose  is  increased, 
however,  the  respiration  becomes  very  slow  and  weak,  and  finally 
ceases  from  paralysis  of  the  centre. 

The  heart  is  somewhat  slower  after  chloral  in  moderate  doses,  but 
scarcely  more  so  than  in  natural  sleep.  There  is  often  some  flushing 
of  the  face  and  head  from  some  obscure  central  action,  but  the  blood- 
pressure  is  little  affected  except  by  large  quantities,  which  reduce  it 
considerably  and  at  the  same  time  cause  marked  slowness  of  the  pulse.2 
The  depression  of  the  blood-pressure  is  caused  in  part  by  paresis  of  the 
vaso-motor  centre,  in  part  by  the  effects  on  the  cardiac  muscle,  and 
possibly  in  part  by  a  direct  action  on  the  muscular  walls  of  the  vessels. 
It  is  much  more  evident  in  poisoning  with  chloral  than  with  the  other 
soporifics,  this  group  presenting  the  same  differences  in  this  respect  as 
the  general  anaesthetics.  In  both  cases  it  is  to  be  noted  that  the  mole- 
cule containing  chlorine  has  the  more  powerful  action  on  the  circula- 
tion. In  chloral  poisoning,  as  in  chloroform,  the  effect  on  the  heart  is 
so  great  as  to  give  rise  to  anxiety  quite  apart  from  the  condition  of  the 
respiration,  and  in  fact  some  cases  of  poisoning  are  said  to  have  termi- 
nated with  failure  of  the  pulse  before  the  respiration,  though  this  is 
unlikely.  The  extreme  weakness  of  the  heart  may,  however,  aid  the 
direct  action  of  the  drug  in  its  effects  on  the  respiratory  centre.  The 
alterations  in  the  heart  are  similar  to  those  produced  by  chloroform, 
the  auricular  contractions  becoming  weak  earlier  than  the  ventricular, 
and  some  dilatation  occurring  in  both  chambers. 

Locally,  chloral  has  an  irritant  action  when  applied  in  concentrated 
solution  and  this  leads  occasionally  to  nausea  and  vomiting  when  it  is 
prescribed  with  insufficient  fluid.  This  irritant  action  induces  redness 
and  even  vesication  when  chloral  is  applied  to  the  skin  ;  it  is  said  to 
corrode  \vhen  applied  to  unprotected  surfaces,  and  certainly  possesses 
antiseptic  properties  like  chloroform.  It  is  rapidly  absorbed  from  the 
stomach  and  carried  to  the  central  nervous  system  where  it  is  taken  up 
by  the  cells  until  they  contain  more  than  the  blood  corpuscles  or  the 
cells  of  other  organs  such  as  the  liver.  Liebreich  introduced  chloral  as 
a  hypnotic  in  the  belief  that  it  was  decomposed  in  the  blood  and  chlor- 
oform liberated,  but  this  has  been  shown  to  be  erroneous,  no  chloroform 
being  found  in  the  blood  or  expired  air  after  chloral.  Chloral  has  no 

1  The  statement  is  made  that  the  reflex  irritability  is  at  first  increased  in  the  frog, 
but  this  may  be  attributed  rather  to  the  remote  effects  of  the  local  irritation  than  to  the 
direct  action  on  the  cord. 

2  Some  investigators  have  stated  that  small  quantities  of  chloral  increase  the  arterial 
tension  at  first,  but  this  must  be  very  transient,  if  present  at  all. 


SOPORIFICS— CHLORAL.  189 

action  on  muscle  or  nerve  in  the  living  animal,  but  when  it  is  applied 
to  the  exposed  nerve  it  first  irritates  and  later  paralyzes  it,  and  injected 
directly  into  the  artery  of  a  muscle  it  causes  immediate  rigor.  The 
temperature  falls  after  the  administration  of  chloral  from  the  lessened 
muscular  movement,  and  perhaps  from  the  increased  output  of  heat 
through  the  dilated  skin  vessels. 

The  effects  of  chloral  on  the  tissue-change  have  been  recently  inves- 
tigated and  found  to  correspond  very  closely  to  those  of  chloroform. 
Thus  fatty  degeneration  of  various  organs  has  been  produced  by  the  pro- 
longed administration  of  chloral  and  of  chloralamide,  and  the  increase 
in  the  nitrogen,  phosphates  and  sulphur,  especially  of  the  unoxidized 
sulphur,  in  the  urine  points  to  augmented  destruction  of  the  proteids 
of  the  body,  together  with  imperfect  oxidation.  The  acidity  of  the 
urine  is  much  increased  by  the  presence  of  urochloralic  acid.  The 
excessive  production  of  this  acid  in  the  tissues  has  been  said  to  be  the 
cause  of  the  alterations  in  the  metabolism,  and  as  a  matter  of  fact 
Kleine  has  found  that  the  addition  of  alkaline  carbonates  to  the  food 
prevents  these  effects  of  chloral.  Chloral  was  formerly  supposed  to 
lead  to  glycosuria,  but  this  has  been  shown  to  be  erroneous,  the  redu- 
cing substance  in  the  urine  being  urochloralic  acid,  and  not  sugar.  In 
addition  to  this  effect  on  the  tissues  generally,  less  oxygen  is  absorbed 
and  less  carbonic  acid  excreted  owing  to  the  diminished  muscular 
movement. 

Chloral  is  reduced  in  the  tissues  to  trichlorethyl  alcohol  (CC1HCH2- 
OH),  which  combines  with  glycuronic  acid  to  form  urochloralic  acid,  and 
is  excreted  in  this  form  in  the  urine.  Some  escapes  by  the  kidneys 
unchanged,  however,  and  some  is  thrown  into  the  stomach,  and  this 
may  account  for  the  nausea  and  discomfort  felt  after  awaking  in  some 
cases. 

The  other  hypnotics  of  this  series,  with  the  exception  of  chloralose, 
correspond  exactly  with  chloral  as  far  as  their  action  on  the  central 
nervous  system  is  concerned.  The  chief  difference  in  their  effects  is 
seen  in  the  circulation  and  metabolism,  which  are  comparatively  little 
affected  by  those  which  do  not  possess  substituted  chlorine  atoms. 

Paraldehyde  and  Sulphonal  do  not  affect  the  heart  directly,  although 
they  may  cause  a  slight  acceleration  of  the  pulse  through  their  depres- 
sant action  on  the  inhibitory  centre.  They  lessen  the  metabolism  through 
their  action  on  the  central  nervous  system,  but  produce  no  such  marked 
alteration  in  the  proteid  decomposition  as  follows  the  administration  of 
chloral.  Paraldehyde  resembles  alcohol  in  its  effects,  though  it  is  a 
much  more  powerful  narcotic  and  rarely  induces  any  symptoms  of  ex- 
citement. Very  large  quantities  of  sulphonal  and  paraldehyde  have 
been  taken  without  fatal  results,  and  in  fact  without  any  more  serious 
consequences  than  prolonged  unconsciousness,  so  that  they  are  much 
safer  narcotics  than  chloral.  Paraldehyde,  however,  has  a  most  un- 
pleasant odor  and  a  hot,  burning  taste,  which  renders  its  administra- 
tion somewhat  difficult.  In  addition  it  is  excreted  in  part  by  the 
lungs,  though  mainly  in  the  urine,  and  the  odor  remains  in  the  breath 


190  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

for  some  time  after  the  patient  awakens.  The  insolubility  of  sulphonal 
in  water  renders  its  absorption  very  slow  and  imperfect,  and  sleep  is 
therefore  late  in  following  its  administration,  while,  on  the  other  hand, 
depression,  drowsiness,  and  lack  of  energy  are  often  complained  of  the 
day  after.  There  is  some  evidence  that  sulphonal  exercises  a  dele- 
terious effect  on  the  liver,  for  the  relation  of  urea  to  the  total  nitrogen 
of  the  urine  is  changed  and  the  metabolism  of  the  purine  bodies  is 
also  affected. 

The  use  of  sulphonal,  especially  when  prolonged,  has  led  in  some 
cases  to  a  series  of  symptoms,  the  most  characteristic  of  which  is  the 
appearance  in  the  urine  of  a  reddish-brown  pigment,  hsematoporphyrin, 
an  iron-free  product  of  the  decomposition  of  haemoglobin.  This  occurs 
most  frequently  in  anaemic  women,  and  is  accompanied  by  constipation, 
pain  in  the  stomach  region  and  vomiting,  weakness  and  ataxia,  confusion 
and  partial  paralysis,  and  eventually  by  suppression  of  the  urine  or  by 
collapse  and  death.1  Hsematoporphyrin  occurs  in  traces  in  the  urine  of 
the  rabbit  normally  and  in  much  larger  quantities  after  the  animal  has 
been  treated  with  sulphonal  (Neubauer).  Its  appearance  in  the  human 
urine  appears  due  to  some  obscure  change  in  the  blood,  and  not  to  de- 
rangement of  the  renal  functions,  although  in  one  case  the  kidneys  were 
found  to  be  diseased,  and  in  animals  the  prolonged  administration  of 
sulphonal  often  causes  albumin  and  casts  in  the  urine,  while  hemorrhages 
in  the  kidneys  have  been  produced  in  them  by  the  administration  of  only 
a  few  doses.  The  amount  of  hsematoporphyrin  in  the  urine  is  some- 
times very  large  ;  in  one  case  Tyson  and  Croftan  found  that  the  quantity 
passed  in  one  day  indicated  the  destruction  of  one  seventeenth  of  the 
total  haemoglobin  of  the  body.  Very  large  doses  of  sulphonal  are  said 
to  produce  convulsive  movements  in  animals,  while  ordinary  ones  cause 
sleep  and  subsequent  drowsiness.  Sulphonal  is  decomposed  in  the  body 
and  is  excreted  largely  as  ethylsulphonic  acid  in  the  urine,  in  which 
traces  of  the  unchanged  substance  have  also  been  found.  The  decom- 
position is  a  slow  process,  however,  for  Kast  found  sulphonal  in  the 
blood  many  hours  after  its  administration.  The  ethylsulphonic  acid 
seems  to  have  no  action  whatever  in  itself,  so  that  the  narcosis  is  due 
to  the  unchanged  molecule  of  sulphonal. 

Sulphonal  seems  to  have  some  deleterious  action  on  the  heart  when 
used  for  long  periods,  and  is  a  much  less  certain  hypnotic  in  cases  of 
cardiac  disease  than  in  other  conditions. 

Butylchloral,  or  Crotonchloral,  was  said  by  Liebreich  to  possess  a  specific 
analgesic  or  anaesthetic  action  on  the  nerves  of  the  face  and  head,  but  this 
has  been  shown  to  be  incorrect  by  v.  Mering,  and,  as  its  effects  are  identical 
with  those  of  chloral  in  almost  all  respects,  crotonchloral  seems  entirely 
superfluous. 

Chloralamide,  or  chloralformamide,  has  been  introduced  in  the  hope  that 
the  stimulant  action  of  the  formainide,  which  is  formed  by  its  decomposition, 
would  counteract  the  depression  of  the  circulation  caused  by  chloral  alone. 
From  blood-pressure  experiments  it  would  seem  that  chloralamide  fulfils 

1  Occasionally  the  hsematoporphyrin  appears  several  days  after  a  single  dose  of  sul- 
phonal or  its  allies,  sometimes  after  an  interval  of  one  or  two  weeks. 


SOPORIFICS—CHLORAL.  191 

those  expectations,  and  has  little  or  no  action  on  the  circulation  except  in 
poisonous  doses.  It  is  said  to  be  less  irritant  than  chloral  in  the  stomach, 
but  to  be  somewhat  slower  and  less  certain  in  its  effects.  Chloral  is  formed 
by  its  decomposition  in  the  body,  and  is  excreted  as  urochloralic  acid,  arid 
fatty  degeneration  has  been  observed  after  its  prolonged  administration. 
On  the  whole  it  would  seem  to  possess  the  cerebral  action  of  chloral,  with- 
out producing  its  effects  on  the  circulation. 

Amylene  Hydrate,  01  limethylethylcarbinol,  has  been  advised  as  a 
hypnotic,  and  is  more  closely  allied  to  paraldehyde  in  its  effects  than 
to  any  of  the  others.  It  is  twice  or  thrice  as  powerful  a  hypnotic  as  paral- 
dehyde, however,  while  it  is  only  one  half  as  strong  as  chloral.  It  is  said  to 
depress  the  heart  more  than  paraldehyde,  but  less  than  chloral,  and  to  pro- 
duce excitement  and  convulsions  in  the  carnivora,  but  not  in  the  herbivora. 
Even  in  man,  it  causes  excitement  more  frequently  than  most  other  sopori- 
fics, and  Harnack  and  Meyer  state  that  it  first  stimulates  and  then  depresses 
the  respiratory  centre  as  well  as  other  parts  of  the  central  nervous  system, 
and  that  it  induces  a  very  marked  fall  in  the  temperature.  The  cardiac  and 
voluntary  muscle  is  first  increased  in  efficiency  and  then  depressed.  It  has 
little  or  no  effect  on  the  general  metabolism,  and  is  excreted  in  the  urine  in 
combination  with  glycuronic  acid  in  the  rabbit,  but  seems  to  undergo  com- 
plete combustion  in  the  tissues  of  the  dog  and  in  man.  It  is  less  certain  in 
its  action  than  chloral  but  has  not  received  so  wide  a  trial  as  it  would  seem 
to  merit.  A  combination  of  chloral  and  amylene  hydrate  has  been  intro- 
duced under  the  name  of  Dormiol,  but  offers  no  advantages  over  chloral. 

Trional  and  Tetronal  are  very  similar  to  sulphonal  in  their  chemical 
structure,  and  have  practically  identical  results  with  it  in  therapeutics, 
although  their  action  on  animals  is  somewhat  more  powerful.  In  some  cases 
of  treatment  with  trional  hsematoporphyrin  has  been  found  in  the  urine. 

Urethane  would  possess  all  the  advantages  of  the  others  with  none  of 
their  disadvantages  were  not  its  effect  on  man  much  weaker  and  less  con- 
stant. In  many  cases  it  is  an  almost  perfect  hypnotic,  easily  taken  in  solu- 
tion, producing  light  sleep  with  no  after-effects,  but  in  others  it  seems  to 
have  little  or  no  hypnotic  effect.  It  is  oxidized  in  the  body  to  urea. 
Hedonal  appears  to  have  a  greater  hypnotic  effect  than  urethane,  but  also 
fails  to  induce  sleep  in  a  considerable  proportion  of  cases.  It  is  followed  by 
no  after-effects  and  is  oxidized  in  the  body  in  the  same  way  as  urethane. 

Chloralose  acts  much  more  like  morphine  than  like  chloral,  depressing 
the  psychical  functions,  while  increasing  the  reflexes  until  convulsions  re- 
sembling those  of  strychnine  may  be  produced.  The  heart  is  comparatively 
little  affected,  and  the  respiration  remains  strong  unless  very  large  doses  are 
given.  In  man  it  induces  sleep,  which  is  sometimes  attended  by  distinctly 
exaggerated  reflexes  however,  especially  when  large  doses  are  given.  Some 
of  the  other  compounds  of  chloral  with  the  sugar  series  seem  to  promise 
more  satisfactory  results. 

Bromoform  has  anaesthetic  properties  like  chloroform,  but  is  not  volatile 
enough  for  inhalation.  Of  late  years  it  has  been  used  internally  in  whooping- 
cough,  and  in  this  relation  it  is  important  to  remember  that  it  gives  rise  to  fatty 
degeneration  when  taken  continuously.  A  number  of  cases  of  alarming  poison- 
ing in  children  have  been  recorded  from  its  use.  It  has  also  been  used  occa- 
sionally in  insomnia. 

Bromal  (CBr3COH)  differs  in  several  respects  from  chloral  in  its  action. 
In  animals  its  injection  is  followed  by  restlessness  and  excitement,  and  then 
by  stupor,  which  is  often  accompanied  by  dyspnoea,  and  ends  in  failure  of 
the  respiration,  or  in  convulsions.  The  pupil  is  much  contracted,  and  pro- 
fuse salivation  is  observed.  It  acts  on  the  heart  like  chloral  but  is  much 
more  poisonous,  and  is  scarcely  used  in  therapeutics. 

Chloretone  resembles  chloral  in  most  respects,  but  is  less  liable  to  irritate 
the  stomach  and  does  not  appear  to  depress  the  circulation  to  the  same  ex- 
tent. Very  large  doses  have  been  swallowed  without  producing  any  untoward 


192  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

symptoms,  but  the  hypnotic  effect  is  obtained  by  the  use  of  smaller  doses 
than  are  necessary  in  the  case  of  chloral.  Like  chloral,  chloretone  has  some 
virtues  as  an  antiseptic,  and  in  addition  it  paralyzes  the  terminations  of  the 
sensory  nerves  when  it  is  applied  locally  and  has  proved  of  value  as  a  local 
anaesthetic. 

Veronal  appears  to  be  practically  devoid  of  action  except  on  the  central 
nervous  system,  inducing  natural  sleep  in  small  doses  without  any  subsequent 
depression.  Larger  quantities  cause  prolonged  sleep  and  the  patient  suffers  from 
drowsiness  and  fatigue  next  day.  It  acts  in  smaller  quantities  than  any  of  the 
older  hypnotics. 

Neuronal  and  Isopral  have  been  introduced  so  recently  that  little  opportu- 
nity has  been  afforded  for  their  study.  Animal  experiments  indicate  their  pos- 
sessing a  stronger  hypnotic  action  than  chloral,  and  satisfactory  results  are 
reported  in  the  cases  in  which  they  have  been  used  in  therapeutics.  The  pres- 
ence of  chlorine  in  the  molecule  of  isopral  suggests  that  it  may  have  some  dele- 
terious action  on  the  circulation  and  metabolism,  and  the  presence  of  bromine 
in  neuronal  is  also  to  be  regarded  as  a  drawback.  Isopral  resembles  chloretone 
in  possessing  some  local  anaesthetic  power. 

Tolerance  is  soon  acquired  for  each  of  these  drugs,  and  when  it  is 
developed  for  one,  large  doses  of  any  of  the  others  are  required  in 
order  to  produce  sleep.  Tolerance  for  alcohol  also  involves  the  use  of 
larger  quantities  of  the  hypnotics,  and  in  fact  often  leads  to  the  com- 
plete failure  of  any  except  the  most  powerful. 

Not  infrequently  the  hypnotics  lead  to  skin  eruptions,  especially 
when  used  for  some  time.  These  assume  various  forms,  the  most  com- 
mon being  of  the  erythema  order,  but  among  others  urticaria,  purpura, 
papular  eruptions  and  blisters  occur. 

Habit.  —  Prolonged  abuse  of  chloral  leads  to  a  condition  somewhat 
resembling  that  seen  in  chronic  alcoholism  or  morphinism,  and  marked 
by  general  depression  and  cachexia,  with  impairment  of  the  mental 
powers,  digestive  disturbance  and  exanthemata.  The  sudden  with- 
drawal of  the  drug  in  these  cases  has  sometimes  led  to  symptoms  re- 
sembling those  of  delirium  tremens,  which  are  especially  dangerous 
here  owing  to  the  fatty  degeneration  of  the  heart  which  may  be  present. 

A  few  cases  of  sulphonal  habit  have  also  been  reported. 

PREPARATIONS. 

CHLORALUM  HYDRATUM  (U.  S.  P.),  CHLORAL  HYDRAS  (B.  P.)  (CC13- 
CH(OH)2  or  (CC13OOH  +  H2O),  a  crystalline  solid,  of  a  characteristic  fruity  odor, 
and  hot,  acrid  taste,  readily  soluble  in  water,  alcohol,  ether  and  oils,  is  almost 
invariably  prescribed  in  dilute  solution  in  syrup.  Its  deliquescent  properties 
preclude  its  use  in  most  of  the  solid  preparations,  and  its  irritant  effects  con- 
traindicate  hypodermic  injection.  Dose,  0.5-2  G.  (10-30  grs.),  which  may 
be  repeated  if  necessary,  in  one  or  two  hours. 

SYRUPUS  CHLORAL  (B.  P.),  $-2  fl.  drs.  (one  drachm  contains  10  grains  of 
chloral). 

PARALDEHYDUM  (U.  S.  P.,  B.  P.)  (C6H12O3),  a  colorless  fluid  of  strong, 
characteristic  odor  and  burning  taste.  It  may  be  prescribed  in  brandy  and 
water,  or  in  water  up  to  10%,  or  in  capsules.  Dose,  1-4  c.c.  (15-60  m.). 

SULPHONAL  (B.  P.),  SULPHONMETHANUM  (U.  S.  P.)  ((CH3)2C(SO2C2H5)2),  a 
crystalline  powder,  without  taste  or  odor.  It  may  be  prescribed  in  powder  form 
to  be  taken  one  to  two  hours  before  retiring,  but  is  soluble  in  hot  water  or  milk, 


SOPORIFICS-  CHLORAL.  193 

and  when  given  in  solution  acts  more  rapidly  and  leaves  no  confusion  after- 
ward. It  is  prescribed  in  doses  of  1-2  G.  (15-30  grs.). 

Sulphonethylmethanum  (U.  S.  P.)  trional  (CH3-C2H5'C-(SO2C2H5)2)  resembles 
sulphonal,  but  is  more  soluble  and  has  a  bitter  taste.  Dose,  1-2  G.  (15-30  grs.). 

Butylchloral  Hydras  (B.  P.),  or  Croton  chloral  (CH3CHC1CC12CH(OH)2), 
resembles  chloral  and  is  prescribed  in  the  same  way,  but  generally  in  smaller 
doses— 0.3-1  G.  (5-15  grs.). 

JEthylis  Carbamas  (U.  S.  P.),  urethane  (CO'OC2H5'NH2),  colorless  crystals, 
odorless,  with  a  cool,  saline  taste,  very  soluble  in  water,  alcohol,  and  ether. 
Dose,  1-5  G.  (15-75  grs.). 

Bromoformum  (U.  S.  P.)  (CHBr3),  a  heavy,  transparent,  colorless  liquid  with 
an  ethereal  odor  and  a  taste  like  that  of  chloroform,  very  little  soluble  in  water, 
but  readily  soluble  in  alcohol.  Dose,  0.2  c.c.  (3  mins.). 

Chloralformamidum  (U.  S.  P.),  or  chloralamide  (CC13CHOHNH -COH),  a 
white  crystalline  powder  with  a  faintly  bitter  taste ;  prescribed  in  powder  or  in 
solution  in  water  or  spirit.  Dose,  1-2  G.  (15-30  grs.). 

Nonofficial. 

Tetronal  resembles  sulphonal  closely,  and  may  be  prescribed  in  the  same  dose 
and  form. 

Amyleni  Hydras  ((CH3)2COHCH2CH3),  a  colorless  liquid  of  pungent  taste,  and 
of  an  odor  somewhat  resembling  camphor.  It  may  be  prescribed  in  capsules,  or 
up  to  10%  in  water  flavored  with  liquorice  extract.  Dose,  3-5  c.c.  (40-80  mins.). 

Hedonal,  a  crystalline  powder  with  a  taste  resembling  that  of  menthol,  very 
slightly  soluble  in  water.  Dose,  2  G.  (30  grs.)  in  powder  or  tablets. 

(fhloretone  (CC13C(CH3)2OH),  colorless  crystals  with  a  strong  camphoraceous 
odor,  slightly  soluble  in  water,  very  soluble  in  alcohol ;  it  may  be  prescribed 
in  aqueous  solution  (about  1  per  cent.)  or,  better,  in  tablets.  Dose,  0.3-1  G. 
(5-15  grs.). 

Veronal  (C2H5)2C(CONH)2CO,  colorless  crystals  with  a  faint  bitter  taste,  solu- 
ble in  145  parts  of  water ;  prescribed  in  powders  or  tablets,  to  be  dissolved  in 
warm  water  or  milk.  Dose,  0.3-1  G.  (5-15  grs.). 

Neuronal  (C2H5)2BrOCONH2,  crystals  with  a  bitter  taste  resembling  that  of 
menthol,  soluble  in  115  parts  of  water  ;  prescribed  in  the  same  way  as  veronal 
in  doses  of  0.5-2.0  G.  (5-30  grs.). 

Isopral  (C2H3C13CHOH),  white  crystals  with  a  camphoraceous  odor  and  aro- 
matic biting  taste,  soluble  in  30  parts  of  water  ;  prescribed  in  doses  of  0. 5-0.75  G. 
(5-8  grs.). 

Therapeutic  Uses.  —  These  drugs  are  chiefly  used  to  produce  rest  and 
sleep  in  cases  of  insomnia  and  in  almost  every  form  of  nervous  ex- 
citement. Until  the  discovery  of  the  therapeutic  value  of  chloral, 
opium  was  used  in  most  of  these  cases,  and  when  sleeplessness  is  due 
to  pain  it  is  still  preferable  to  the  more  modern  remedies,  which  have 
comparatively  slight  influence  on  acute  pain,  except  in  very  large  doses. 
But  in  delirium,  mania  and  convulsions  of  various  kinds,  their  action 
on  the  nerve  centres  is  preferable  to  that  of  opium,  especially  where 
these  convulsions  are  of  spinal  origin  or  of  a  reflex  nature ;  thus,  in 
strychnine  poisoning  and  in  tetanus,  chloral  is  of  great  value,  although 
in  the  former  it  may  have  to  be  reinforced  by  chloroform  during  the 
convulsions.  In  delirium  from  fever  or  from  ursemic  intoxication  and 
similar  causes,  comparatively  small  doses  often  produce  most  satisfac- 
tory results,  and  in  various  spasmodic  affections,  such  as  cough,  asthma, 
and  choreic  movements,  it  is  exceedingly  useful.  Chloral  has  also  been 
advised  to  lessen  the  pains  of  labor. 

Most  of  the  soporifics  have  been  used  more  or  less  extensively  as 
13 


194  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

hypnotics  in  simple  insomnia  and  in  insanity,  but  when  the  disturb- 
ance assumes  a  more  violent  character  there  is  a  disposition  to  return 
to  the  use  of  chloral,  as  at  once  the  speediest  and  surest  remedy  of  the 
whole  group.  When  there  is  any  reason  to  suspect  fatty  degeneration 
of  the  heart,  however,  some  hypnotic  which  does  not  contain  chlorine 
ought  to  be  substituted  for  it,  and  paraldehyde,  sulphonal,  hedonal 
and  veronal  have  been  introduced  in  succession  to  supply  the  need. 
Chloral  is  often  prescribed  along  with  opium,  and,  when  thus  com- 
bined, smaller  quantities  of  each  drug  are  required  than  would  be 
necessary  if  either  were  prescribed  alone,  and  the  sleep  following  is 
very  deep  and  restful.  It  is  also  used  very  often  to  reinforce  the 
action  of  the  bromides. 

Other  Narcotics  which  for  some  purposes  may  be  substituted  for  the 
members  of  the  chloral  group  are  alcohol,  opium  and  its  alkaloids, 
bromides,  hyoscine  and  cannabis  indica. 

Chloral  has  been  used  externally  as  a  counter-irritant  and  antiseptic, 
but  is  more  expensive  than  many  other  equally  efficacious  remedies. 
Chloretone  solution  is  an  efficient  local  anaesthetic  on  wounded  sur- 
faces, and  has  been  recommended  in  cases  of  gastric  irritation  and 
vomiting,  which  it  relieves  by  paralyzing  the  terminations  of  the  sen- 
sory nerves  in  the  mucous  membrane  of  the  stomach. 

In  cases  of  acute  Poisoning  with  chloral  the  treatment  consists  in 
the  immediate  evacuation  of  the  stomach  by  the  stomach  tube.  Emet- 
ics are  of  less  value  owing  to  the  depression  of  the  medullary  centres. 
The  patient  ought  to  be  kept  warm  and  caifeine  or  strychnine  may  be 
given  as  a  respiratory  stimulant,  while  the  complete  failure  of  the 
breathing  has  to  be  met  by  artificial  respiration.  In  acute  poisoning 
with  the  other  members  of  the  series  the  same  general  treatment  is  to 
be  applied,  but  the  prognosis  is  much  more  favorable  than  after  chloral ; 
in  one  case  in  which  100  G.  of  sulphonal  were  swallowed,  the  recov- 
ery was  attributed  by  the  attendant  physician  to  copious  enemata  of 
water.  In  chronic  poisoning  with  sulphonal,  the  withdrawal  of  the 
drug  is  generally  all  that  is  required.  In  the  chloral  habit,  the  with- 
drawal has  to  be  gradual  and  it  may  be  necessary  to  send  the  patient 
to  a  retreat. 

BIBLIOGRAPHY. 
Chloral. 

Liebreich.     Das  Chloral,  ein  neues  Hypnoticum,  Berlin,  1868. 
Lewisson.     Arch.  f.  Anat.  u.  Phys.,  1870,  p.  346. 
Harnack  u.   WitkowskL     Arch.  f.  exp.  Path.  u.  Pharm.,  xi.,  p.  1. 
Heidcnhain.     Pfl tiger's  Arch.,  iv.,  p.  557,  and  xxvi.,  p.  137. 

v.  Mering.     Arch.  f.  exp.  Path.  u.  Pharm.,  iii.,  p.  185.    Zts.  f.  phys.  Chem.,  vi.j  p 
480. 

Preisendorfer.     Deutsch.  Arch.  f.  klin.  Med.,  xxv.,  p.  40. 

Loewy.     Pfliiger's  Arch.,  xlvii.,  p.  601. 

Taniguti.     Virchow's  Arch.,  cxx.,  p.  121. 

Remertz.     Inaug.  Diss.,  Halle,  1893.     Fortschr.  der  Med.,  1893,  p.  265. 

Harnack  u.  Kleine.     Ztsch.  f.  Biol.,  xxxvii.,  p.  417. 

Kraepehn.     Beeinflussung  psychischer  Vorgiinge  durch  Arzneimittel.,  p.  209, 

Paraldehyde. 

Cervello.  Arch.  f.  exp.  Path.,  xvi.,  p.  265. 
Albertoni.  Arch.  Ital.  d.  Biol.,  iii.,  p.  197. 
Friedldnder.  Therap.  Monats.,  1893,  p.  144. 


STRYCHNINE-NUX   VOMICA.  195 

Sulphonal. 

Kast.    Berl.  klin.  Woch.,  1888,  p.  309.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi.,  p.  69. 
Smith.     Zts.  f.  phys.  Chem.,  xvii.,  p.  1. 
Friedldnder.     Therap.  Monats.,  1894,  pp.  183  and  370. 
Kast  u.  Weiss.    Berl.  klin.  Woch.,  1896,  p.  621. 
Vanderlinden  u.  Debuck.     Arch,  de  Pharmacodyn. ,  i.,  p.  431. 
Neubauer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliii.,  p.  456. 
Haenel.     Kraepelin's  Psychol.  Arb.,  ii.,  p.  326. 
Tyson  and  Croftan.    Philad.  Med.  Journ.,  1902,  p.  882. 

Amylene  Hydrate,  and  other  Soporifics. 

v.  Mering.     Therap.  Monats.,  1887,  p.  249. 
Friedldnder.     Ibid.,  1893,  p.  370. 

Harnack  u.  Meyer.     Ztschr.  f.  klin.  Med.,  xxiv.,  p.  374. 
Lahousse.     Arch,  de  Pharmacodyn.,  i.,  p.  209.     (Butylchloral. ) 
Manchot.     Virchow's  Arch.,  cxxxvi.,  p.  368. 

Henriot  u.  Hichet.     Arch,  de  Pharmacodyn.,  iii.,  p.  191.     ( Chloralose. ) 
Schmiedeberg.     Arch.  f.  exp.    Path.  u.  Pharm.,  xx.,  p.  203.     (Urethane  and   the 
group  in  general. ) 

Bradbury.     Croonian  Lectures,  Brit.  Med.  Jour.,  1899. 

Houghton  and  Aldrich.     Journ.  Am.  Med.  Ass.,  Sept.  23,  1899.     (Chloretone.) 

Impens.     Arch,  internat.  de  Pharmacodyn.,  viii.,  p.  77.     (Chloretone. ) 

Impens.     Therap.  Monatsh.,  1903,  p.  469.     (Isopral.) 

Fuchs  and  Schultze.     Miinchener  med.  Woch.,  1904,  p.  1102.     (Neuronal.) 

Fischer  and  Mering.    Therapie  der  Gegenwart,  xlv.,  p.  97.      (Veronal.) 

II.     STRYCHNINE  — NUX   VOMICA. 

Strychnine  is  the  chief  alkaloid  occurring  in  several  species  of 
Strychnos,  of  which  the  best  known  are  Strychnos  nux-vomica  and 
Strychnos  Ignatia.  It  is  found  chiefly  in  the  seeds,  and  is  generally 
accompanied  by  the  nearly  related  alkaloid  Brucine. 

A  large  number  of  alkaloids  have  been  found  to  resemble  strychnine  in 
their  action,  such  as  the  Thebaine  found  in  opium,  the  Gelsemine  of  Gelsemium 
sempervirens,  and  the  Calabarine  of  the  Calabar  bean,  while  it  is  difficult  to 
decide  whether  several  others  ought  to  be  classed  with  morphine  or  with 
strychnine. 

Strychnine  seems  to  be  a  quinoline  derivative,  although  its  exact  consti- 
tution is  unknown.  Its  formula  is  C21H22N2O2,  while  that  of  brucine  is 
C23H26N2O4.  They  are  both  derivatives  of  a  substance  of  the  formula 
C15HJ7N2O2,  brucine  differing  from  strychnine  in  having  two  methoxyl 
groups.  It  seems  not  unlikely  that  they  are  both  nearly  related  to  cura- 
rine,  the  alkaloid  of  curara,  which  is  derived  from  some  other  species  of  the 
genus  Strychnos. 

The  alkaloids  of  the  strychnine  group  have  a  powerful  stimulant 
action  on  the  central  nervous  system,  especially  on  the  spinal  cord, 
throughout  the  vertebrate  kingdom. 

Symptoms.  —  In  ordinary  therapeutic  doses  strychnine,  like  other 
bitter  substances  (page  55),  improves  the  appetite  and  often  leads  to  a 
distinct  amelioration  of  the  subjective  symptoms,  the  patient  feeling 
stronger  and  more  hopeful.  The  pulse  is  generally  slower  and  the 
artery  feels  less  compressible.  The  special  senses  are  rendered  more 
acute  by  small  quantities  of  strychnine,  for  differences  can  be  recog- 
nized between  shades  of  color  which  seem  identical  to  the  normal 
vision ;  the  field  of  vision  is  widened,  and  in  certain  conditions  of 
amblyopia  light  is  rendered  much  more  distinct.  In  the  same  way 
the  hearing  seems  to  be  more  acute,  and  the  sense  of  touch  is  much 


196 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


more  delicate.  Some  cases  have  been  noted  in  which  disagreeable  odors 
were  rendered  pleasant  by  strychnine,  but  this  would  seem  to  be  a  rare 
idiosyncrasy.  In  cases  of  poisoning  with  strychnine,  the  first  symp- 
tom is  often  a  more  acute  perception  of  external  objects  by  the  senses, 
especially  by  the  sense  of  touch,  but  this  is  not  generally  observed  by 
the  patient,  whose  first  complaint  is  of  a  feeling  of  stiffness  in  the  mus- 
cles of  the  neck  and  face.  This  is  soon  followed  by  an  increased 
reflex  reaction,  so  that  a  slight  touch  causes  a  violent  movement,  and 
even  a  sound  or  a  current  of  air  is  sufficient  to  cause  a  sudden  start. 
The  increased  reflex  irritability  is  generally  accompanied  by  some  rest- 
lessness, and  animals  sometimes  seem  to  make  attempts  to  escape  from 
bright  light.  Some  tremor  or  involuntary  twitches  may  be  observed  in 
the  limbs,  and  then  a  sudden  convulsion  occurs  in  which  all  the  muscles 
of  the  body  are  involved,  but  in  which  the  stronger  extensor  muscles 
generally  prevail.  In  animals,  the  head  is  drawn  back,  the  hind  limbs 
extended,  and  the  trunk  forms  an  arch  with  its  concavity  backwards 
(opisthotonos)  (Fig.  13).  In  man,  the  same  convulsions  are  seen  and 


FIG.  13. 


A  rabbit  during  a  strychnine  convulsion. 


are  accompanied  by  strong  contraction  of  the  face  muscles,  producing 
a  hideous  grin  which  has  been  called  the  risus  sardonicus.  The  res- 
piratory muscles  are  involved  in  the  general  paroxysm  and  the  blood 
rabidly  becomes  deoxygenated,  as  is  shown  by  the  blue  cyanotic  color 


FIG.  14. 


A  rabbit  when  the  strychnine  spasm  is  passing  off.    The  head  is  supported  to  prevent  it  falling  on 

the  table. 

of  the  lips  and  face  in  man.  The  muscles  feel  hard  and  firm  at  the 
commencement  of  the  convulsion,  but  very  soon  a  tremor  may  be  made 
out,  which  becomes  more  distinct,  and  after  a  few  intermittent  contrac- 
tions the  animal  sinks  back  in  a  condition  of  prostration  (Fig.  14).  The 


STRYCffiflNE-NVX  VOMlCA.  19? 

respiration  generally  returns,  and  becomes  fairly  regular  for  a  short 
time.  Immediately  after  a  convulsion  the  reflex  irritability  may  be 
low,  but  it  soon  regains  its  former  exaggerated  condition  and  a  second 
convulsion  occurs,  exactly  resembling  the  first.  Mammals,  as  a  gen- 
eral rule,  succumb  after  two  or  three  convulsions,  the  respiration 
failing  to  return  after  the  spasm.  In  some  cases,  however,  the  con- 
vulsions become  shorter  and  the  intervals  of  quiescence  longer,  the 
respiration  becomes  weak,  the  reflex  irritability  gradually  lessens 
and  the  animal  dies  from  asphyxia.  In  frogs,  where  the  breathing 
can  be  dispensed  with  for  long  periods,  the  alternation  of  convul- 
sions and  periods  of  quiescence  may  continue  for  hours  or  days,  but 
these  are  of  the  same  general  character  as  those  described  in  mammals. 
After  very  large  quantities  no  convulsions  may  occur,  the  animal  dying 
almost  immediately  of  asphyxia  from  paralysis  of  the  central  nervous 
system. 

Action. — The  whole  character  of  the  intoxication  points  to  an  affection 
of  the  Central  Nervous  System,  and  it  has  been  found  that  the  symptoms 
are  unaltered  when  the  drug  is  prevented  from  reaching  the  peripheral 
nerves  and  muscles.  The  chief  symptoms  arise  from  the  spinal  cord, 
for  the  convulsions  are  at  least  as  well  marked  in  frogs  and  mam- 
mals in  which  the  brain  has  been  destroyed  or  severed  below  the 
medulla  oblongata.  At  the  same  time  the  brain  is  also  believed  to  be 
affected,  though  to  a  less  degree.  The  intellect  in  man  remains  un- 
clouded until  the  end,  except  for  the  asphyxia  produced  by  the  stop- 
page of  the  respiration ;  the  patient  is  perfectly  conscious  of  his 
condition,  and  suffers  excruciating  pain  from  the  violent  contractions  of 
the  muscles.  It  is  said  that  the  increased  reflex  may  be  inhibited  to  a 
certain  extent  by  the  will,  but  during  the  convulsions  no  strength  of 
will  can  cope  with  the  irritability  of  the  spinal  cord. 

The  special  senses  are  rendered  more  acute  by  small  doses  of  strych- 
nine, and  this  is  apparently  due  to  its  effects  on  the  central  ner- 
vous system  in  the  case  of  touch,  taste  and  smell,  but  there  is  reason 
to  believe  that  the  increase  in  the  field  of  vision  and  the  increased 
sensitiveness  to  slight  differences  in  light  are  to  be  attributed  to  its 
acting  on  the  cells  of  the  retina  and  not  to  cerebral  changes.  For 
when  strychnine  salts  are  injected  in  the  temple  or  applied  to  the  con- 
junctiva, the  sight  of  the  corresponding  eye  is  improved  while  the 
other  remains  unaffected  (Filehne);  if  the  strychnine  acted  centrally  it 
could  do  so  only  by  being  carried  to  the  brain  by  the  blood,  but  this 
would  affect  each  hemisphere  equally.  The  affection  of  one  eye  only 
is  explained  by  the  strychnine  diffusing  through  the  lymph  spaces,  and 
this  is  said  to  have  occurred  in  the  case  of  various  dyes  which  were 
applied  in  the  same  way  and  were  then  found  in  the  retina. 

As  regards  the  effects  of  strychnine  on  the  motor  areas  of  the  brain 
some  difference  of  opinion  exists,  although  the  majority  of  those  who 
have  investigated  the  subject  hold  that  the  irritability  of  the  motor 
parts  of  the  cortex  is  distinctly  increased  except  during  a  con- 
vulsion. 


198  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

The  convulsions  are,  as  has  been  stated,  of  spinal  origin.  It  has 
been  shown  in  addition  that  they  are  reflex,  that  provided  no  stimulus 
reaches  the  cord  from  without,  no  convulsion  occurs.  As  has  been 
already  remarked,  the  convulsions  are  preceded  by  a  stage  of  increased 
reflex,  and  in  fact  the  first  convulsion  is  often  seen  to  follow  a  stimulus, 
such  as  a  blow  or  a  loud  noise.  Afterwards  they  may  seem  to  occur 
without  any  such  impulse,  but  this  is  merely  because  a  very  slight  or 
even  imperceptible  stimulus  is  enough  to  induce  them.  For  ex- 
ample, a  slight  contraction  of  a  muscle  may  induce  a  convulsion, 
as  is  seen  very  frequently  in  the  frog,  where  a  very  slight  stimulus, 
in  itself  apparently  too  weak  to  cause  a  convulsion,  is  followed  by 
an  ordinary  reflex  contraction,  and  this  leads  to  a  spasm.  The 
absence  of  convulsions  when  external  stimuli  are  cut  oif  may,  how- 
ever, be  demonstrated  conclusively  in  various  ways.  Thus  Pouls- 
son  found  that  a  frog  dipped  in  cocaine  solution  underwent  no  con- 
vulsions after  strychnine,  the  cocaine  used  being  sufficient  to  paralyze 
the  sensory  terminations,  but  not  to  have  any  direct  effect  on  the  cord. 
Claude  Bernard  showed  this  even  more  conclusively  by  dividing  all 
the  posterior  roots  of  the  spinal  nerves  in  the  frog  and  then  injecting 
strychnine,  when  no  convulsions  occurred  except  when  the  ends  of  the 
cut  roots  were  stimulated.  The  convulsions  therefore  follow  only  on 
the  passage  of  an  impulse  from  without  to  the  spinal  cord,  and  are 
merely  a  further  development  of  the  preceding  stage  of  exaggerated 
reflex  irritability.  The  characteristic  feature  of  strychnine  poisoning 
is  thus  the  response  to  external  stimuli.  In  the  unpoisoned  animal 
the  reflex  movement  following  a  stimulus  is  always  of  the  same  kind  ; 
for  example,  if  the  leg  of  a  decapitated  frog  be  dipped  in  acid  it  makes 
certain  movements  to  withdraw  the  limb,  and  no  matter  how  often  the 
irritation  be  repeated,  the  same  movements  are  produced,  though  it  is 
true  that  if  stronger  acid  be  used  the  movement  is  more  violent  and  a 
greater  number  of  muscles  are  involved.  In  this  movement  certain 
muscles  contract  while  their  antagonists  are  inhibited,  for  example 
in  drawing  the  toe  away  from  an  irritant  the  anterior  muscles  of  the  leg 
contract,  while  the  gastrocnemius  is  relaxed.  The  same  irritation  which 
produced  in  the  unpoisoned  animal  a  simple  withdrawal  of  the  limb 
causes  after  strychnine  stronger  and  more  extensive  contractions,  and 
the  movement  is  not  confined  to  the  two  hind  legs  but  spreads  over  the 
whole  body.  All  the  muscles  contract  together,  there  being  no  in- 
hibition of  antagonists  and  the  resultant  movement  has  thus  quite  a  dif- 
ferent character  ;  the  gastrocnemius  being  stronger  than  the  anterior  leg 
muscles,  the  foot  is  extended  and  thrust  against  the  irritant  instead  of 
being  withdrawn  from  it.  When  an  external  stimulus  is  sufficient  to 
cause  a  convulsive  movement  in  a  poisoned  animal,  the  contraction  is 
always  maximal ;  a  stronger  stimulus  produces  no  greater  effect.  It  must 
be  remarked  that  the  reflex  response  to  different  forms  of  stimuli  is  not 
equally  altered  by  strychnine.  The  irritation  of  the  frog's  foot  by  very 
slowly  acting  substances,  such  as  dilute  acids,  may  be  followed  by  an  ordi- 
nary reflex  movement,  while  a  sudden  shock  causes  a  violent  convulsion. 


STRYCHNINE—  NUX  VOMICA. 


199 


FIG.  15. 


Many  attempts  have  been  made  to  define  the  exact  seat  of  the  strych- 
nine action  in  the  spinal  cord  and  although  the  question  is  not  abso- 
lutely determined,  there  are  strong  grounds  for  the  belief  that  the  cells 
of  the  anterior  horn  are  not  necessarily  involved  in  the  strychnine 
action.  (Fig.  15.)  For  when  strych- 
nine is  applied  in  solution  to  the  cord  of 
the  frog  at  the  level  of  the  cells  connected 
with  the  nerves  to  the  fore  limbs,  irrita- 
tion of  the  foot  produces  an  ordinary  re- 
sponse in  the  hind  limbs,  while  the  anter- 
ior part  of  the  body  remains  motionless  ; 
that  is,  strychnine  has  not  penetrated  to 
the  cells  connected  with  the  hind  limbs. 
Irritation  of  the  fore  limbs,  on  the  other 
hand,  produces  tetanus  not  only  of  these, 
but  also  of  the  hind  limbs,  although  the 
motor  cells  of  the  hind  limbs  have  been 
shown  to  be  outside  the  poisoned  area. 
Tetanus  can,  therefore,  be  produced  in 
parts  whose  motor  cells  are  unpoisoned, 
yet  the  increased  strength  of  the  con- 
traction would  seem  to  point  to  an  affec- 
tion of  these  cells.  The  explanation 
may  be  that  the  impulse  reaching  the 
motor  cell  is  stronger,  and  that  the 
latter  simply  transmits  this  more  power- 
ful impulse  as  it  would  a  weaker  one. 
A  theory  that  covers  'the  phenomena 
hitherto  recognized  is  that  the  impulse 
traveling  up  a  nerve  in  an  unpoisoned 
frog  may  pass  through  a  large  number 
of  paths  in  the  cord,  but  meets  with 
resistance  in  all  save  one.  It  therefore 
passes  along  the  path  of  least  resistance, 
and  produces  a  definite  result  by  acting 
on  a  fixed  series  of  nerve  cells.  After  Diagram  of  the  spinal  cord  of  the  frog. 

A-B,   the  part  of  the  cord  exposed  to 

strychnine  the  same  impulse  reaching  the  strychnine,    s-c,  the  unaffected  zone. 

t  n      i        n    .1  ,i  n  i      An  impulse  reaching  the  cord  through  the 

COrd  finds  all  the  paths  equally  easy,  and,    sensory  fibre  #  passes  to  the  motor  cells 

therefore,  divides  and  affects  a  very  much  °  "0 


larger  number  of  motor  cells.     At  the  ^ 

same  time  less  energy  is  spent  in  passing 

through  resistance,  a  greater   force  re-  m°tor  ceils  F'  F\  which  are  under  the 

o  111  influence  of  the  poison,  but  also  in  those 

mains  tO  be  expended  On   the  motor  Cells,    supplied  by  FF,  which  have  been  shown 
,  ,  ,  -,  .  .       ,1  n  to  be  free  from  the  strychnine  action. 

and  the  muscular  movement  is,  therefore, 

much  exaggerated.  It  is  quite  impossible  at  present  to  state  the  exact 
point  at  which  strychnine  removes  the  resistance  to  the  passage  of 
impulses.  It  does  not  seem  located  in  the  cells  of  the  anterior  horn,  for, 
as  has  been  mentioned,  tetanus  may  be  elicited  when  they  are  certainly 


200  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

not  affected  by  strychnine.  On  the  other  hand,  the  cells  of  the  spinal 
ganglion  are  not  requisite,  for  stimulation  of  the  posterior  root  sets  up 
tetanus  in  frogs  poisoned  with  strychnine,  in  which  the  section  of  the  root 
has  thrown  the  spinal  ganglion  out  of  action.  The  poison  must,  there- 
fore, act  at  some  point  between  the  entrance  of  the  sensory  root  into  the 
cord  and  the  motor  cells.1  It  must  be  remarked  that  while  the  resist- 
ance is  much  reduced,  it  is  not  entirely  removed  and  the  ordinary  path 
is  still  somewhat  more  easily  traversed  than  the  others,  for  very  weak 
irritation  often  causes  an  ordinary  reflex  response  in  the  frog,  while 
slightly  stronger  stimulus  throws  it  into  opisthotonos.  Baglioni  has 
recently  shown  that  a  single  stimulus  is  not  sufficient  to  cause  complete 
tetanus,  but  that  the  movement  iriduced  by  the  first  shock  leads  to 
secondary  stimuli  arising  from  the  joints  and  tendons  which  are  moved ; 
the  arrival  of  these  secondary  stimuli  in  the  cord  maintains  it  in 
activity,  and  the  muscles  consequently  remain  contracted  until  the 
cord  is  fatigued  and  refuses  to  react  to  the  persistent  stimuli  from  the 
periphery.  The  muscles  then  relax  and  an  interval  of  quiescence  fol- 
lows until  the  cord  has  recovered  its  irritability. 

Besides  the  spinal  cord,  all  other  regions  in  which  simple  reflex  can 
be  produced  are  aifected  by  strychnine.  Thus  the  medullary  centres 
are  thrown  into  the  same  condition,  and  their  responses  to  stimuli  are 
equally  exaggerated ;  but  they  are  in  constant  receipt  of  impulses,  and 
strychnine  by  increasing  the  efficiency  of  these  augments  the  tone  of 
the  medulla  oblongata,  when  it  is  given  in  small  quantities.  The  in- 
creased activity  of  the  higher  reflex  areas  may  in  fact  lessen  or  inhibit 
the  irritability  of  the  cord,  so  that  the  reflex  response  from  the  latter 
may  be  strengthened  by  the  removal  of  the  brain  and  medulla  oblon- 
gata. 

Artificial  respiration  has  been  shown  to  delay  the  onset  of  convul- 
sions in  animals,  but  it  is  still  an  open  question  whether  this  is  due  to 
the  better  aeration  of  the  blood  (Osterwald)  or  to  the  effects  of  the 
mechanical  movements  (Gies  and  Meltzer). 

The  stimulation  of  the  spinal  cord  by  strychnine  is  followed  by  de- 
pression and  paralysis.  Even  during  the  first  stage  the  stimulation  is 
mixed  with  depression,  for  though  a  more  violent  response  is  induced 
by  a  sensory  stimulus,  this  cannot  be  repeated  so  often  as  in  the  nor- 
mal frog,  as  the  cord  becomes  fatigued  more  readily.  The  sensory  part 
of  the  spinal  cord  seems  to  be  paralyzed  somewhat  earlier  than  the 
motor  cells,  but  these  also  lose  their  irritability  after  a  time  and  no 
further  movement  can  be  elicited  either  by  reflex  or  by  direct  stimu- 
lation of  the  cord. 

Strychnine  seems  to  have  no  direct  action  on  the  voluntary  Muscles  ; 
it  is  stated  that  minute  quantities  increase  their  tone,  that  is,  render 

1  The  nuclei  of  the  cells  of  the  anterior  horn  in  the  spinal  cord  have  been  found 
somewhat  enlarged  in  frogs  poisoned  with  strychnine,  but  this  is  observed  also  after 
electric  stimulation,  and  seems  to  indicate  hyperactivity  of  the  cell,  which  need  not 
necessarily  be  due  to  direct  action  of  the  poison  on  it. 


STRYCHNINE—NUX   VOMICA.  201 

them  more  tense,  so  that  they  are  prepared  for  immediate  contraction, 
but  this  is  due  to  action  on  the  cord  and  not  on  the  muscle  fibres. 

The  Terminations  of  the  Motor  Nerves  are  paralyzed  by  large  doses 
of  strychnine  in  the  same  way  as  by  curara.  This  effect  is  scarcely 
seen  in  mammals,  as  central  paralysis  always  precedes  it  and  destroys 
life,  but  in  some  species  of  frogs  the  nerve  ends  are  paralyzed  before 
the  central  nervous  system.  This  paralysis  is  not  due  to  the  exhaus- 
tion of  the  nerve  ends  through  the  tetanus,  but  is  a  direct  action  on  the 
terminations,  although  the  exhaustion  may  contribute  to  the  result. 

The  Respiration  is  quickened  and  deepened  by  small  quantities  of 
strychnine,  especially  when  the  centre  is  depressed  by  the  previous 
administration  of  a  narcotic.  During  the  convulsions  the  breathing  is 
arrested  by  the  violent  contraction  of  the  diaphragm  and  the  other 
respiratory  muscles,  but  during  the  intermissions  it  continues  fairly 
regular.  After  one  or  two  spasms  it  often  fails  to  be  reinstated,  and 
the  animal  dies  of  asphyxia ;  in  other  experiments  it  undergoes  a 
gradual  diminution  in  rate  and  strength,  and  eventually  ceases  from 
gradual  paralysis  of  the  centre. 


FIG.  16. 


The  blood-pressure  tracing  of  a  cat  under  strychnine,  showing  the  marked  rise  during  a  spasm. 
A,  quiescence ;  Bt  convulsion  commencing. 

In  frogs  very  large  quantities  slow  and  weaken  the  Heart  by  direct 
action,  but  in  mammals  it  is  not  directly  affected  by  strychnine,  though 
the  stimulation  of  the  inhibitory  centre  leads  to  a  slightly  slower 
rhythm.  Occasionally  acceleration  of  the  heart  is  seen  during  and 
after  a  convulsion,  and  this  is  probably  due  to  the  muscular  exertion, 
and  may  be  compared  to  that  seen  after  violent  movements  in  ordinary 
life.  The  stimulation  of  the  Vaso-motor  Centre  leads  to  a  constriction 
of  the  peripheral  arterioles.  Strychnine  in  small  quantities  therefore 
slows  the  heart  and  raises  the  blood-pressure,  unless  in  exceptional 
cases  where  the  slowing  of  the  heart  is  so  great  as  to  counteract  the 
contraction  of  the  arterioles. 

1  According  to  Impens  (Arch,  internat.  de  Pharmacodyn. ,  VI.,  p.  156),  this  occurs 
in  the  rabbit  only  when  sufficient  strychnine  is  injected  to  cause  spasms. 


202  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

During  the  convulsions  the  blood-pressure  is  raised  to  an  extreme 
height,  partly  owing  to  the  activity  of  the  vaso-motor  centre  and  per- 
haps partly  from  the  blood  being  pressed  out  of  the  abdominal  organs 
and  the  muscles  by  their  violent  contraction.  Immediately  after  a 
convulsion  the  blood-pressure  falls,  probably  from  the  exhaustion  of 
the  centre.  The  blood -pressure  remains  elevated  much  longer  in  cura- 
rized  than  in  uncurarized  animals,  which  would  seem  to  indicate  that 
the  fall  in  pressure  is  partly  due  to  the  substances  produced  by  mus- 
cular activity.  The  constriction  seems  to  affect  mainly  the  internal 
vessels,  while  those  of  the  skin  and  perhaps  of  the  muscles  are  dilated, 
and  the  blood  current  is,  therefore,  deflected  largely  from  the  internal 
organs  to  the  skin  and  limbs.  The  cause  of  the  dilatation  of  these 
vessels  is  probably  stimulation  of  vaso-dilator  areas  in  the  medulla. 

The  heart  continues  to  beat  long  after  the  breathing  has  ceased,  and 
if  artificial  respiration  be  had  recourse  to,  may  remain  active  an  in- 
definite time. 

In  the  Alimentary  Tract,  strychnine  has  the  same  action  as  any  other 
bitter  substance,  and  it  produces  a  flow  of  saliva  and  increased  appetite 
if  taken  before  meals.  (See  Stomachic  Bitters,  page  55.)  It  seems 
to  be  absorbed  from  the  intestine  mainly.  After  absorption  it  probably 
increases  the  activity  of  the  central  apparatus  regulating  the  movement 
of  the  bowel,  but  the  results  in  man  and  in  most  animals  have  not  been 
ascertained  with  exactness. 

Metabolism.  —  Strychnine  produces  an  enormous  activity  of  the  mus- 
cles, and,  therefore,  increases  very  greatly  the  consumption  of  oxygen 
and  the  output  of  carbonic  acid.  This  increased  excretion  of  carbonic 
acid  occurs,  though  to  a  less  extent,  even  when  the  muscular  contrac- 
tion has  been  previously  eliminated  by  curara,  and  must,  therefore,  be 
due  in  part  to  the  contraction  of  the  involuntary  muscle  of  the  vas- 
cular walls  and  perhaps  to  the  increased  metabolism  of  the  central 
nervous  system. 

The  augmentation  of  the  oxidation  in  the  tissues  is  accompanied  by 
an  increased  formation  of  heat,  which  would  lead  to  a  rise  in  the  tem- 
perature of  the  body  were  it  not  counteracted  by  an  equal  or  even 
greater  increase  in  its  dissipation  through  the  skin.  The  result  of  the 
interaction  of  these  two  factors  is  that  in  spite  of  an  increased  warmth 
production  the  internal  temperature  is  generally  lowered  in  rabbits, 
while  a  slight  rise  in  the  thermometer  is  sometimes  seen  in  dogs  and 
cats.  The  skin  temperature,  on  the  other  hand,  rises  considerably 
because  more  blood  flows  through  it  than  usual. 

In  the  frog,  the  administration  of  strychnine  is  often  followed  by 
glycosuria.  This  does  not  seem  to  occur  in  adult  mammals  but  is 
sometimes  observed  in  young  dogs,  in  which,  as  in  frogs  at  certain 
seasons,  there  is  a  large  accumulation  of  glycogen  in  the  liver.  Demant 
states  that  strychnine,  even  in  small  quantities,  causes  the  glycogen  of 
the  liver  and  muscles  to  disappear ;  the  increased  muscular  movement 
and  the  disturbance  of  the  respiration  are  probably  the  explanation  of 
both  of  these  phenomena. 


STRYCHNINE-NUX    VOMIGA.  203 

Strychnine  is  eliminated  in  the  urine  chiefly.  Its  excretion  begins 
soon  after  its  injection,  but  is  exceedingly  slow,  and  the  reaction  is 
often  given  by  the  urine  for  3-8  days  afterwards.  Traces  of  the  alka- 
loid also  appear  in  the  stomach  after  its  hypodermic  injection,  and  it  is 
not  improbable  that  some  of  it  undergoes  oxidation  in  the  tissues. 

The  statement  that  a  tolerance  can  be  acquired  for  strychnine  when 
it  is  given  for  some  time  has  been  proved  quite  incorrect  (Hare). 

The  action  of  strychnine  is  almost  identical  throughout  the  vertebrate 
kingdom.  Man  is  more  susceptible  than  other  mammals,  and  young  ani- 
mals are  more  refractory  than  adults,  perhaps  owing  to  the  less  developed 
condition  of  the  central  nervous  system.  The  domestic  fowl  tolerates  com- 
paratively large  quantities  without  symptoms.  Among  the  invertebrates, 
the  reaction  to  strychnine  seems  to  vary  considerably ;  in  the  medusae 
symptoms  of  increased  irritability  and  typical  convulsions  are  produced  by 
it  (Romanes),  while  in  the  crab  slightly  increased  movement  may  be  observed 
occasionally,  but  the  chief  effect  seems  to  be  depression  and  eventual 
paralysis.  The  snail  is  said  to  be  practically  immune.  The  temperature  of 
the  animal  has  some  influence  on  the  action  of  the  poison,  for  frogs  react 
more  readily  when  heated  than  when  kept  in  the  cold,  the  heat  seeming  to 
increase  the  activity  of  the  central  nervous  system. 

Brucine,  the  second  alkaloid  of  nux  vomica,  resembles  strychnine  closely 
in  action  but  is  much  weaker,  from  30  to  40  times  as  large  a  dose  being  re- 
quired to  produce  the  same  effect.  It  differs  from  strychnine  also  in  possess- 
ing a  much  more  powerful  action  on  the  nerve  terminations  in  voluntary 
muscle,  especially  in  some  species  of  frog.  It  is  credited  with  weak  local 
anaesthetic  properties. 

Calabarine  and  gelsemine  are  chiefly  of  interest  as  impurities  which 
occur  along  with  the  more  important  alkaloids  of  the  Calabar  bean  and  of 
Gelsemium,  while  thebaine  forms  a  connecting  link  between  the  opium  alka- 
loids and  strychnine,  and  will  be  discussed  along  with  the  morphine  series  ; 
it  seems  to  stand  midway  between  strychnine  and  brucine  in  toxicity. 

PREPARATIONS. 

Nux  Vomica  (U.  S.  P.,  B.  P.),  the  seeds  of  Strychnos  nux-vomica,  contains 
0.9-2  per  cent,  of  strychnine  and  0.7-1.5  per  cent,  of  brucine,  along  with 
tannin,  which  gives  a  dark  green  coloration  with  iron  salts.  The  powdered 
bean  is  occasionally  prescribed  in  doses  of  0.06-0.25  G.  (1-4  grs.). 

EXTRACTUM  Nucis  VoMiCE  (U.  S.  P.,  B.  P.),  0.015-0.06  G.  (\-\  gr.). 

Fluidextractum  Nucis  Vomicce  (U.  S.  P.),  0.06-0.3  c.c.  (1-5  mins.). 

Fluidextractum  Nucis  Vomicce  Liquidum  (B.  P.),  1-3  mins. 

TINCTURA  Nucis  VOMKLE  (U.  S.  P.,  B.  P.),  0.3-1  c.c.  (5-15  mins.). 

Strychnina  (U.  S.  P.,  B.  P.),  0.002-0.004  G.  (-^-^  gr.). 

STRYCHNINE  NITRAS  (U.  S.  P.),  0.002-0.004  G.  UV-rV  gr.). 

STRYCHNIN M  SULPHAS  (U.  S.  P.),  0.002-0.004  G.  (fa-ifa  gr.). 

STRYCHNINE  HYDROCHLORIDUM  (B.  P.),  -fa-fa  gr. 

Liquor  Strychnine  Hydrochloridi  (B.  P.)  (1  per  cent.),  2-8  mins. 

Ferri  et  Strychninse  Citras  (U.  S.  P.),  0.06-0.2  G.  (1-3  grs.). 

Syrupus  Ferri,  Quininse,  et  Strychninse,  Phosphatum  (U.  S.  P.),  4-8  c.c.  (1-2 
fl.  drs.). 

Syrupus  Ferri  Phosphatis  cum  Quinina  et  Strychnina  (B.  P.),  £-1  fl.  dr. 

The  extract  is  generally  prescribed  in  pill  form,  while  strychnine  sulphate 
or  hydrochlorate  may  be  given  in  solution,  pill  or  tablet ;  where  rapid  action 
is  desired,  it  is  injected  subcutaneously.  The  tincture  is  largely  used  as  a 
stomachic  bitter,  and  the  iron  preparations  in  conditions  of  general  debility. 

Brucina  (not  pharmacopoeial),  0.005-0.03  G.  (TV~z  gr.)- 


204  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Therapeutic  Uses.  —  Strychnine  is  used  largely  for  its  local  action  on 
the  digestive  organs  as  a  stomachic  bitter,  and  is  generally  prescribed 
in  the  form  of  the  tincture  or  one  of  the  extracts  for  this  purpose,  as 
in  this  way  it  is  much  less  liable  to  absorption  than  when  given  as  an 
alkaloidal  salt.  It  may  be  combined  with  the  cinchona  preparations 
Or  with  one  of  the  simple  bitters. 

Small  quantities  of  strychnine  are  of  benefit  in  many  ill-defined  con- 
ditions of  weakness,  cachexia  and  "  want  of  tone "  generally.  The 
results  are  probably  partly  due  to  its  stomachic  effects  in  increasing 
appetite  and  digestion,  but  the  action  on  the  central  nervous  system 
cannot  be  overlooked.  The  slight  increase  in  the  irritability  of  the 
cord  probably  leads  to  an  improvement  in  almost  all  of  the  nutritive 
functions  through  increasing  the  contraction  of  the  vessels  and  pro- 
ducing greater  activity  of  the  muscles.  In  this  way  strychnine  per- 
haps deserves  the  name  of  "  tonic  "  more  than  most  of  the  drugs  to 
which  it  is  applied.  It  must  be  added  that  in  a  number  of  conditions 
in  which  strychnine  is  ordinarily  employed,  Cabot  failed  to  find  any 
change  in  the  blood-pressure  after  its  use. 

As  a  stimulant  to  the  central  nervous  system *  strychnine  has  found 
wide  application  in  almost  every  form  of  paralysis,  and  as  long  as  dis- 
tinct anatomical  lesions  of  the  central  nervous  axis  are  absent,  it  may 
be  of  benefit ;  for  instance,  it  is  often  valuable  in  lead  poisoning ;  but 
where  the  continuity  of  the  axis  is  broken  by  haemorrhage  or  by  the 
destruction  of  the  nerve  cells,  little  improvement  is  to  be  anticipated 
from  its  use,  though  it  may  serve  to  delay  or  prevent  the  atrophy  of 
peripheral  nerves  and  muscles  in  some  of  these  cases.  When  the  par- 
alysis is  due  to  an  inflammatory  process,  strychnine  is  to  be  used  with 
the  greatest  care,  or  is  perhaps  better  avoided  entirely  as  long  as  the 
irritation  is  present,  as  it  seems  to  increase  and  prolong  the  inflamma- 
tion when  used  early  in  these  cases. 

Strychnine  is  used  as  a  respiratory  stimulant  in  some  forms  of  pul- 
monary disease  in  which  it  is  desirable  to  increase  the  respiration  or  to 
provoke  coughing.  It  has  been  advised  in  failure  of  the  respiration 
during  anaesthesia,  and  is  certainly  more  likely  to  be  beneficial  than 
the  great  majority  of  drugs  suggested  for  this  purpose.  Too  large 
doses  must  not  be  injected  in  these  cases,  however,  as  strychnine 
paralyzes  the  respiratory  centre  itself  when  given  in  excess.  In  other 
forms  of  poisoning  in  which  the  respiratory  centre  seems  in  danger, 
and  in  shock,  strychnine  may  also  be  of  service,  especially  when  it  is 
injected  hypodermically.  Other  respiratory  stimulants  which  may  be 
substituted  for  strychnine  for  some  purposes  are  caffeine  and  atropine. 

In  amaurosis  or  amblyopia  unassociated  with  atrophy  of  the  optic 
nerve,  and  even  in  commencing  atrophy,  strychnine  has  frequently  im- 
proved the  vision.  In  many  cases  it  fails  to  produce  any  benefit,  and 
the  exact  conditions  in  which  improvement  can  be  looked  for  are  un- 
known. 

1  Other  central  nervous  stimulants  are  Caffeine,  Atropine,  Camphor. 


STEYCHNINE—NUX  VOMICA.  205 

Strychnine  seems  to  be  of  benefit  in  some  cases  of  heart  disease 
and  is  often  supposed  to  have  a  direct  action  on  that  organ.  Any  im- 
provement which  may  be  produced  by  it,  however,  must  be  attributed 
to  the  constriction  of  the  vessels,  and  the  indications  for  its  use  would 
seem  to  be  a  low  blood-pressure ;  Crile  denies  it  any  value  in  the  treat- 
ment of  the  low  blood-pressure  of  shock,  however.  The  increased 
arterial  tension  may  be  prejudicial  to  the  heart  in  some  conditions, 
through  increasing  the  resistance  against  which  it  has  to  contract.  The 
heart-rhythm  is  also  slower  after  strychnine  has  been  administered, 
owing  to  stimulation  of  the  inhibitory  centre.  A  similar  effect  follows 
the  use  of  aconite,  veratrum,  and  digitalis,  though  in  the  case  of  the 
last  it  is  accompanied  by  changes  in  the  heart  which  are  not  induced  by 
the  others. 

Strychnine  is  said  to  be  of  value  in  chronic  alcoholism  in  lessening  the 
depression  which  forms  one  of  the  chief  difficulties  in  the  treatment. 

The  other  alkaloids  of  this  series  do  not  seem  to  have  any  proper- 
ties which  would  entitle  them  to  a  position  in  therapeutics. 

Poisoning.  —  In  cases  of  strychnine  poisoning,  the  first  treatment 
consists  in  the  evacuation  of  the  stomach  by  means  of  emetics,  or  bet- 
ter by  the  stomach  tube  ;  it  may  be  necessary  to  give  chloroform  as  the 
attempt  to  pass  the  tube  is  often  followed  by  violent  convulsions. 
Preparations  of  tannic  acid,  such  as  strong  tea,  may  be  given  in  order 
to  form  the  insoluble  tannate,  which,  however,  must  be  removed  as 
quickly  as  possible,  as  it  is  broken  up  by  the  acid  gastric  juice  and 
the  strychnine  is  rapidly  absorbed.  To  combat  the  convulsions,  de- 
pressants to  the  central  nervous  system  should  be  given,  and,  although 
chloral  is  usually  advised,  chloroform  or  ether  is  often  preferable. 
It  is  unnecessary  to  produce  deep  anaesthesia,  a  few  whiffs  of  chloro- 
form being  often  sufficient  to  allay  the  convulsions.  The  advantage 
of  the  anaesthetics  over  chloral  is  that  they  can  be  removed  if  any 
symptoms  of  strychnine  paralysis  appear.  Opium  has  been  suggested, 
but  is  not  nearly  so  efficacious  in  strychnine  poisoning  as  members  of 
the  methane  series.  If  the  paralysis  comes  on,  artificial  respiration 
may  be  attempted,  although  the  poison  is  excreted  too  slowly  from 
the  organism  to  permit  of  much  hope  of  recovery. 

BIBLIOGRAPHY. 

Mayer.     Sitzungsber.  der  Wiener  Acad.,  Ixiv.,  1871,  p.  657. 
Denys.     Arch.  f.  exp.  Path.  u.  Pharm.,  xx.,  p.  306. 
Poulsson.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi.,  p.  22. 

Wood.     Journ  of  Physiol.,  xiii.,  p.  870. 

Harnaek.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlix.,  p.  157. 

Delezenne.     Arch,  de  Physiol.  (5),  vi.,  p.  899. 

Honghton  and  Muirhead.     Medical  News,  1895,  i.,  p.  612. 

Eeichert.     Med.  News,  1893,  i.,  p   369. 

Mays.     Journal  of  Phys.,  viii.,  p.  391. 

Hoyyes.     Arch.  f.  exp.  Path.  u.  Pharm.,  xvi.,  p.  97. 

Walton.     Journal  of  Phys.,  iii.,  p.  308. 

Filehne  and  his  pupils.     Pfliiger's  Archiv,  Ixxxiii.,  pp.  369,  397,  403. 

Sinyer.     Arch.  f.  Ophthalmologie,  1.,  p.  665, 


206  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Osterwald.     Arch.  f.  exp.  Path.,  xliv.,  p.  451. 

Verworn  and  Baglinni,     Arch.  f.  [Anat.  u.]  Phys.,  1900,  p.  385,  Supplem.,  pp.  152, 
193.     Ztschr.  f.  allg.  Physiol.,  ii.,  p.  556,  iv.,  p.  113. 

Meltzer,  Salant  and  Gies.     Journ.  of  Exp.  Med.,  vi..  p.  107  ;  Amer.  Journ.  of  Phys., 
ix.,  p.  1. 

Sherrington.     Proc.  Koyal  Society,  Ixxvi.,  B. 

Hare.     Amer.  Journ.  of  Physiol.,  v.,  p.  333. 

In  addition,  strychnine  was  studied  by  Magendie,  Cl.  Bernard  and  Orfila  and  thei; 
works  ought  to  be  consulted  for  the  earlier  history  of  the  poison. 

III.     OPIUM  SERIES. 

Opium  has  been  used  in  medicine  since  a  very  remote  period,  and 
although  many  substitutes  have  been  proposed  for  it  of  late  years,  it 
still  occupies  a  position  of  its  own  in  therapeutics.  It  is  the  dried 
juice  of  the  Papaver  somniferum,  a  poppy  which  is  grown  chiefTyln 
India,  China,  Egypt,  Persia  ancl  Asia  Minor,  but  has  been  cultivated 
in  colder  climates  and  is  said  to  produce  a  more  powerful  opium 
there.  Opium  owes  its  activity  to  a  large  number  of  alkaloids,  of 
which  Morphine  is  the  most  important.  Others  are  Codeine,  Pseudo- 
morphine,  Thebaine,  Codamine,  Laudanine,  Laudanosine,  Papaverine, 
Meconidine,  Lanthopine,  Cryptopine,  Protopine,  Papaveramine,  Rhoea- 
dine,  Narcotine,  Oxynarcotine,  Narceine,  Hydrocotarnine,  Gnoscopine 
and  Tritopine.  Many  of  these,  however,  occur  only  in  traces.  The 
total  amount  of  alkaloids  in  opium  varies  from  about  5—25  per  cent., 
and  different  specimens  may  contain  very  different  quantities  of  each 
alkaloid ;  for  instance,  morphine  may  vary  from  2.7-22.8  per  cent. 
The  average  percentage  of  morphine  is  10,  of  narcotine  6,  papaverine 
1,  codeine  0.5,  thebaine  0.3  and  narceine  0.2 ;  the  others  occur  in  too 
small  quantity  to  have  any  influence  on  the  action  of  the  crude  drug. 
The  alkaloids  are  found  in  opium  in  combination  with  meconic,  lactic 
and  sulphuric  acids.  The  empirical  formulae  of  most  of  the  alkaloids 
have  been  determined,  those  of  the  most  important  being  morphine 
(C17HlrN"O3),  codeine  (C18H21NO3),  narcotine  (C22H23NO7),  papaverine 
(C20H21NO4),  thebaine  (C19H21NO3).  The  constitutions  of  several  are 
known,  and  these  appear  to  be  isoquinoline  derivatives,  but  the  structural 
formulae  of  morphine  and  codeine  are  still  undecided,  and  the  majority 
of  investigators  are  now  inclined  to  believe  that  they  do  not  belong  to 
the  pyridine-quinoline  alkaloids.  Morphine  apparently  contains  phe- 
nanthrene  (C14H10),  a  hydrocarbon  isomeric  with  anthracene,  combined 
with  a  nitrogenous  radicle  which  is  probably  morpholine  ; l  it  possesses 
two  hydroxyls  and  the  substitution  of  one  of  these  by  methoxyl  forms 
codeine.  Thebaine  and  several  others  appear  to  be  closely  related  to 
morphine,  and  it  is  not  improbable  that  they  may  all  eventually  prove 
to  be  more  nearly  related  than  their  reactions  would  seem  to  indicate 
at  present. 

The  action  of  opium  is  due  to  the  large  amount  of  morphine  con- 

1  The  formula  for  morphine  accepted  as  most  probable  at  present  is 

/N(CH=)-CH' 

CH2 


OPIUM  SERIES.  207 

tained  in  it,  the  other  alkaloids  being  present  in  too  small  quantity  to 
modify  its  effects  appreciably.  Morphine  acts  chiefly  on  the  central 

*  *  — ,  -  * —  AJ ,1,1     IIT— •rTyMMMtarfta^-TrriTa-irrMin-^T^'*'^"^**^^^^ 

nervous  system  although  it  also  affects  some  peripheral  organs,  such 
as  the  intestine.  Its  action  varies  considerably  in  different  animals, 
and  it  is  therefore  necessarv  to  consider  its  effects  at  some  length  upon 
the  different  classes. 

Symptoms. — The  Frog  is  remarkably  tolerant  of  morphine,  no  change 
whatsoever  following  the  injection  of  quantities  which  would  cause  dis- 
tinct symptoms  in  man.  The  first  symptoms  elicited  are  a  diminution 
of  the  spontaneous  movements ;  the  animal  sits  still  unless  disturbed, 
but  then  moves  in  a  perfectly  normal  manner.  Later  the  movements 
become  clumsy  and  ill-coordinated,  and  at  the  same  time  they  are 
elicited  less  easily.  At  a  somewhat  more  advanced  stage  of  the  intox- 
ication, the  animal  makes  no  movement  when  placed  in  abnormal 
positions,  as  on  its  back,  which  indicates  that  it  has  lost  entirely  its 
power  of  preserving  its  equilibrium.  The  spinal  cord  maintains  its 
irritability,  but  in  a  lower  degree  than  usual,  as  is  shown  by  the  reflex 
movements  being  weaker  than  in  the  unpoisoned  frog.  This  condition 
may  last  for  several  hours,  when  a  series  of  symptoms  of  an  entirely 
different  nature  appear.  The  reflex  response  to  irritation  is  distinctly 
depressed  during  the  first  stage,  but  in  this  second  phase  it  begins  to 
return,  and  eventually  a  condition  of  exaggerated  reflex  irritability 
sets  in.  This  development  first  affects  the  muscles  of  respiration, 
but  soon  spreads  over  the  whole  spinal  cord,  so  that  the  condition 
comes  to  resemble  exactly  that  noted  in  strychnine  poisoning,  except 
that  the  frog  seems  more  easily  exhausted  than  after  moderate  quanti- 
ties of  strychnine.  The  same  tetanic  contractions  of  the  muscles  are 
to  be  seen,  however,  with  opisthotonos  and  cessation  of  the  respiration, 
interrupted  by  periods  of  quiescence  and  exhaustion.  The  animal 
may  recover  from  this  stage,  in  which  case  it  again  passes  through  the 
stage  of  depression,  but  it  frequently  dies  during  it  from  exhaustion 
and  paralysis  of  the  central  nervous  system. 

In  Mammals,  morphine  produces  symptoms  resembling  those  seen  in 
the  frog,  first  depression  of  the  voluntary  movements,  and  later  a  marked 
increase  in  the  reflex  irritability.  The  relative  importance  of  these  two 
stages  differs,  however,  in  the  different  classes,  and  indeed  in  different 
individuals  of  the  same  class.  Thus  in  the  cat  and  in  all  the  other 
felidaB,  and  in  the  horse  and  ass  morphine  seems  rather  to  increase  than 
to  diminish  movement.  The  animal  runs  about  the  room  or  in  a  circle 
and  seems  unable  to  remain  at  rest  for  a  moment.  At  the  same  time  a 
depression  of  the  intelligence  and  of  the  power  of  perception  makes  it- 
self manifest,  for  no  definite  attempts  at  escape  are  made  and  obstacles 
are  not  avoided  so  carefully  as  by  the  unpoisoned  animal.  Eventually 
convulsions  similar  to  those  seen  after  strychnine  are  developed.  In 
the  dog,  on  the  other  hand,  the  depressant  action  of  the  drug  is  the  more 
highly  developed,  at  any  rate  after  small  doses.  The  first  symptom  is 
not  infrequently  vomiting  and  defecation,  and  then  the  animal  passes 


208  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

into  a  light  sleep,  from  which  he  can  be  easily  aroused  by  touching  or 
by  noise,  but  which  rapidly  becomes  deeper,  so  that  greater  force  has 
to  be  used  to  waken  him.  When  once  awakened,  he  seems  to  sleep  less 
heavily  for  a  short  time,  and  a  much  slighter  stimulus  is  enough  to 
arouse  him  if  it  is  applied  soon  afterwards.  When  awakened  he  may 
perform  apparently  voluntary  movements  for  a  short  time,  although 
more  clumsily  than  in  his  normal  state,  but  no  complete  conscious- 
ness is  present,  the  animal  is  stupid  and  drowsy  and  soon  sinks  back 
into  deep  slumber  again.  The  sensation  of  pain  seems  to  be  much 
lessened  but  not  entirely  abolished,  and  reflex  movements  are  diffi- 
cult to  elicit.  After  larger  quantities  an  exaggerated  sensibility  to 
external  stimulation  seems  present,  for  the  animal  starts  convul- 
sively at  loud  sounds  and  on  pinching,  but  when  left  undisturbed  lies 
in  profound  sleep.  The  respiration  is  at  first  quick  and  dyspnoeic,  the 
dog  panting  as  if  after  a  long  run,  but  later  it  becomes  slow  and 
labored ;  the  pupil  is  narrowed ;  the  circulation  seems  less  affected, 
although  a  congestion  of  the  skin  and  mouth  is  often  observed.  The 
stage  of  strychnine-like  convulsions  is  not  developed  in  the  dog, 
although  the  reflex  irritability  may  be  distinctly  increased  by  large 
quantities.  Just  before  the  respiration  finally  ceases,  convulsions 
generally  occur,  but  these  are  asphyxial  in  origin  and  are  not  due  to 
the  direct  action  of  the  alkaloid.  In  the  rabbit  and  other  rodents  the 
symptoms  are  similar  to  those  seen  in  the  dog,  but  the  depression  is 
even  more  marked.  An  increase  in  the  reflex  irritability  to  external 
stimulation  is  also  evident  here,  while  the  respiration  is  slowed  from  the 
beginning.  Small  quantities  of  morphine  produce  drowsiness  in  the 
horse,  ass  or  goat,  larger  quantities  restlessness  and  excitement  which 
may  pass  into  convulsions  and  death. 

In  Birds,  morphine  causes  vomiting,  drowsiness,  sleep  and  stupor, 
with  slow  and  imperfect  respiration,  very  much  as  in  mammals.  It 
has  been  repeatedly  stated  that  pigeons  possess  a  high  degree  of  toler- 
ance for  morphine,  but  this  does  not  seem  correct,  for  though  in  com- 
mon with  all  the  lower  animals  they  are  much  less  susceptible  to  its 
influence  than  man,  the  tolerance  does  not  seem  much  greater  than  that 
of  rabbits  and  dogs  when  the  drug  is  administered  hypodermically.  It 
seems  to  be  absorbed  with  difficulty  from  the  crop. 

In  Man,  small  quantities  of  morphine  lessen  the  voluntary  move- 
ments  and  produce  a  drowsiness  which  soon  passes  into  sleep,  unless 
the  patient  is  continually  aroused  by  his  surroundings.  As  long  as  he 
is  kept  awake,  his  actions  and  movements  show  nothing  abnormal,  but 
it  is  impossible  to  keep  his  attention  directed  to  any  object  for  long, 
and  as  soon  as  he  is  left  to  himself  for  a  few  moments  he  sinks  into 
sleep.  After  small  quantities  there  is  no  difficulty  in  arousing  him ;  in 
fact,  the  sleep  seems  lighter  than  usual  and  may  resemble  rather  a 
state  of  abstraction  or _^f  brown  study  "  In  this  condition  the  im- 
agination is  not  depressed "toTKe  same  extent  as  the  reason,  and  it  is 
often  stated,  therefore,  that  opium  at  first  stimulates  the  intellectual 


OPIUM  SERIES.  209 

powers.  This  is  incorrect,  however  —  the  self-control  and  judgment 
are  lessened,  and  although  the  stream  of  thought  may  seem  more  rapid 
and  the  images  more  vivid  than  usual,  the  logical  sequence  is  lost,  and 
the  condition  may  rather  be  compared  to  dreaming  than  to  a  real  in- 
crease of  the  intellectual  powers.  In  particular,  the  patient  has  often 
no  idea  of  time.  This  stage  of  abstraction  is  not  by  any  means  gen- 
erally observed  and  soon  passes  into  sleep,  but  the  unchecked  imagina- 
tion may  still  persist  in  the  form  of  dreams. 

In  larger  quantities  morphine  produces  deep,  dreamless  sleep,  from 
which  the  patient  is  still  easily  aroused,  but  which  returns  at  once 
when  he  is  left  undisturbed.  When  once  aroused,  he  can  be  kept 
awake  or  can  be  aroused  again  after  a  short  interval  much  more  easily, 
some  time  elapsing  apparently  before  the  same  degree  of  depression  is 
reached  again.  As  the  dose  is  increased,  the  sleep  deepens  into  torpor, 
from  which  he  can  be  wakened  only  with  difficulty,  and  eventually  all 
efforts  to  arouse  his  attention  are  fruitless  and  he  sinks  into  coma, 
which  may  be  reached  very  soon  after  a  large  dose.  During  this 
deeper  sleep  and  coma  the  respiration  is  very  slow,  the  pulse  is  regu- 
lar, full,  and  of  moderate  speed.  The  pupils  are  contracted  to  a  small 
point  and  the  mouth  and  throat  are  dry.  The  face  is  purple  and  con- 
gested, and  the  skin  feels  warm,  although  the  temperature  may  be  low. 
The  breathing  generally  becomes  slower  and  weaker,  and  occasionally 
periodic  (Cheyne-Stokes).  The  cyanosis  increases,  the  pulse  becomes 
smaller  and  often  quicker,  the  pupils  remain  contracted,  but  dilate 
widely  just  before  the  final  arrest  of  the  repiration.  The  heart  con- 
tinues to  beat  feebly  for  a  short  time  afterwards. 

After  small  doses  of  morphine  the  patient  generally  awakes  refreshed, 
and,  save  for  an  occasional  dryness  of  the  throat  and  slight  nausea, 
apparently  quite  normal.  Not  infrequently,  however,  headache  is  com- 
plained of,  and  sometimes  nausea  and  vomiting,  accompanied  by  marked 
depression.  In  rare  cases  delirium,  and  even  convulsions,  have  been 
observed  soon  after  its  injection,  but  these  symptoms  of  excitement  are 
so  rare  in  the  human  subject  as  to  be  classed  as  idiosyncrasies.  Some 
skin  affections,  such  as  itching  and  redness,  are  occasionally  seen  while 
the  action  is  passing  off. 

Action. — The  action  of  morphine  on  the  Central  Nervous  System  seems 
to  consist  then  of  a  mixture  of  stimulation  and  depression,  which  are 
not  equally  marked,  however,  throughout  the  divisions  of  the  central 
axis.  The  depression  seems  to  be  produced  mainly  in  the  brain, 
es£ecmlly  in  those  parts  associated  with  the  higher  intellectual  facul- 
ties, while  the  stimulation  affects  first  the  spinal  cord.  It  seems  lively 
{Eat  in  different  animals  these  two  opposing  influences  prevail  to  vary- 
ing extents,  so  that  in  some  the  stimulant  action  extends  to  the  brain, 
as  in  the  cat,  while  in,  man  thejiepressant  action  dominates  the_wljfile 
central  nervous  system,  at  any  rate  when  moderate  quantities  are  used. 
The  action  on  the  brain  is  elicited  by  smaller  quantities  than  that  on 
the  cord,  so  that  the  first  effect  of  morphine  is  general  intellectual  de- 
pression, while  the  increased  activity  of  the  spinal  functions  is  only 

14 


210  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

elicited  by  very  large  q  uantities.    This  selective  action  of  morphine  is  es- 
pecially evident  in  the  medulla  oblongata,  in  which  certain  centres  are  en- 
tirely paralyzed  before  neighbor  ing  ones  undergo  any  distinct  modification. 
I      Morphine,  therefore,  seems  to  combine  in  itself  the  properties  of  I 
l\ alcohol  and  of  strychnine  ;  like  the  former,  it  depresses  the  functions! 
I  of  attention  and  coordination  of  the  brain,  while,  like  the  latter,  it  in- 
/  creases  the  activity  of  the  spinal  cord. 

The  effect  of  morphine  on  the  Spinal  Cord  has  been  studied  almost 
exclusively  in  the  frog.  The  reflex  irritability  in  these  animals  is  first 
diminished  to  a  slight  extent,  and  then  increased  to  the  same  degree 
as  by  strychnine.  It  seems  difficult  to  believe  that  the  same  drug 
should  cause  first  depression  and  then  stimulation  of  a  function,  but  it 
has  been  shown  in  the  description  of  the  action  of  strychnine  that  all 
the  elements  of  the  spinal  cord  are  not  involved  in  the  changes  pro- 
duced by  that  poison,  and  a  possible  explanation  would  be  that  while 
small  quantities  of  morphine  lessen  the  ability  of  the  motor  cells  to 
give  out  impulses,  larger  quantities  increase  the  activity  of  the  recep- 
tive and  transmitting  cells,  so  as  to  compensate  for  the  depression  of 
the  motor  cells  and  eventually  to  conceal  their  depression  entirely. 

It  will  be  shown  in  the  discussion  of  the  effects  of  morphine  on  the 
respiratory  centre  that  some  grounds  exist  for  the  belief  that  the 
motor  functions  are  depressed  by  morphine,  but  this  explanation  of  its 
action  on  the  cord  must  be  looked  upon  merely  as  a  preliminary  hypoth- 
esis to  account  for  the  phenomena.1 

The  hypothesis  of  opposing  action  on  the  motor  and  sensory  ele- 
ments of  the  cord  would  explain  the  different  results  observed  in  dif- 
ferent classes  of  animals  by  assuming  that  the  depressant  effects  on 
the  motor  apparatus  are  more  developed  in  one  class,  while  in  another 
the  stimulation  of  the  receptive  apparatus  is  the  predominating  feature. 
It  is  to  be  remarked  that  in  all  animals  the  cord  is  less  depressed  than 
in  the  corresponding  stage  of  chloral  poisoning,  for  if  two  animals  are 
poisoned,  the  one  with  morphine,  the  other  with  chloral,  until  no 
voluntary  movements  occur,  the  reflexes  of  the  one  poisoned  with 
morphine  are  always  found  more  active  than  those  of  the  other. 

The  effects  of  morphine  on  the  Brain  are  no  less  difficult  to  account 
for  than  those  on  the  cord.  In  the  frog,  the  symptoms  of  increasing 
depression  correspond  to  those  observed  after  the  removal  in  succession 
of  the  cerebral  lobes,  the  corpora  quadrigemina,  the  cerebellum  and 
the  medulla  oblongata.  In  man,  it  is  often  found  that  comparatively 
small  quantities  are  sufficient  to  deaden  or  even  entirely  remove  the 
pain  of  disease  without  rendering  the  patient  unconscious.  The  in- 
telligence is  not  so  acute  as  normally,  but  he  answers  questions  and 
converses  freely  and  may  even  seem  abnormally  sensitive  to  impres- 
sions caused  by  loud  noises  or  bright  flashes  of  light.  Animals  in  this 
condition  may  be  subjected  without  resistance  to  what  would  ordi- 

1  The  old  explanation,  which  attributed  the  increased  activity  of  the  spinal  cord  to  its 
being  liberated  from  the  inhibitory  action  of  the  brain  through  the  cerebral  depression, 
has  proved  inadequate,  for  total  destruction  of  the  brain  does  not  give  rise  to  the  ex- 
aggerated reflex  movements  elicited  by  morphine  in  the  frog. 


OPIUM  SERIES. 


211 


FIG.  17. 


550 


500 


450 


400- 


350  - 


300  - 


M 


narily  involve  considerable  pain,  provided  the  application  be  not  sud- 
denly made.  If  struck  suddenly,  however,  they  react  as  usual,  and 
remain  apparently  as  sensitive  as  usual  for  some  time.  Morphine 
then  seems  to  lessen  the  power  of  concentrating  the  attention.  As 
long  as  any  stimulus  is  of  constant  strength,  be  it  an  internal  pain  or 
a  noise  or  light,  the  morphinized  individual  remains  unconscious  of  it. 
On  the  other  hand,  a  shock  is  at  once  perceived,  and  the  lethargy  being 
for  the  moment  dispelled,  he  reacts  to  his  surroundings  for  a  short  time, 
but  is  incapable  of  prolonged  attention  and  soon  sinks  into  stupor  again. 

Morphine  in  moderate  quantities  seems  to  have  but  little  effect  on 
the  irritability  of  the  motor  areas  of  the  brain  cortex,  but  in  large 
quantities  it  lowers  and  eventually  abolishes  it.  Exner  found  no 
alteration  in  the  time  elapsing  between  the  perception  of  a  flash  of  light 
and  a  preconcerted  movement,  while  others  have  found  that  the  re- 
action to  a  slight  touch  was  re- 
tarded. This  would  agree  with  the 
hypothesis  introduced  above  —  the 
po\ver  of  summation  is  lessened 
and  slight  stimuli  are  therefore  per- 
ceived more  slowly,  while  a  stronger 
impression  is  perceived  and  acted 
upon  after  the  usual  interval. 

Several  observers  have  investi- 
gated the  relative  sensibility  of  the 
skin  before  and  after  morphine. 
The  method  employed  was  to  meas- 
ure the  smallest  distance  on  the  skin 
at  Avhich  the  person  could  recognize 
two  points  as  distinct.  In  every 
case  it  was  found  that  the  ability  to 
do  this  was  lessened  by  morphine 
owing  to  the  central  depression,  the 
drug  seeming  not  to  have  any  direct 
action  on  the  sensory  organs  them- 
selves. Various  authors  have  ex- 
amined the  cortical  cells  after  mor- 
phine with  the  hope  of  finding  some 
histological  changes  produced  by  it. 
The  results  are  discordant,  how- 
ever, and  alterations  said  to  be 
characteristic  by  one  investigator 
have  been  shown  to  be  due  to  the 
histological  methods  used  by  him. 

Before  closing  the  consideration 
of  the  action  of  morphine  on  the 

central  nervous  system,  it  may  be  well  to  discuss  its  effects  on  the 
Respiration.  y^In  man  and  in  most  other  animals  the  respiration  is 
slowed  by  morphine  from  the  beginning  (Fig.  17),  but  in  "the  dog 


200 


M 


0    10    20 


40    50    60 


Diagram  of  the  volume  of  air  inspired  by  a 
rabbit  during  morphine  narcosis.  J/,  injection 
of  morphine.  The  amount  is  measured  in  c.c. 
along  the  perpendicular,  while  the  time  is  meas- 
ured along  the  horizontal  line.  At  first  about 
540  c.c.  is  inspired  in  2%  minutes,  but  after  the 
injection  of  morphine,  M,  the  volume  falls  to 
about  200  c.c.  and  is  maintained  at  200-300 
throughout  the  experiment.  (After  STURS- 
BERG.  ) 


212  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

there  is  often  a  preliminary  stage  of  rapid,  panting  breathing,  which 
may,  however,  be  secondary  to  the  emetic  and  purgative  effects.  The 
respiration  in  man  is  at  first  somewhat  deeper  than  usual,  but  the  in- 
crease in  the  depth  is  seldom  sufficient  to  counterbalance  the  slowness  of 
the  breathing,  so  that  the  air  inspired  per  minute  is  considerably  re- 
duced ;  in  the  later  stages  it  becomes  shallower  and  is  often  irregu- 
lar. This  irregularity  may  have  a  periodic  character,  a  series  of  deep 
respirations  being  followed  by  several  progressively  weaker  ones  and 
then  by  complete  inactivity  for  several  seconds.  The  breathing  then 
recommences  with  a  very  slight  movement,  followed  by  a  series  in- 
creasing regularly  in  strength  and  then  again  decreasing.  This  form 
of  respiration  (Cheyne-Stokes)  is  seen  in  various  pathological  condi- 
tions and  has  received  different  explanations,  but  is  probably  due  to 
direct  action  on  the  respiratory  centre.  It  has  been  mentioned  already 
that  when  the  animal  is  once  aroused  repeated  movements  are  much 
more  easily  elicited,  and  it  would  seem  probable  that  the  accumulation 
of  carbonic  acid  and  other  poisons  and  the  lack  of  oxygen  in  the  blood 
during  the  pause  eventually  awaken  the  torpid  centre,  which  causes  a 
small  movement.  The  next  movement  is  larger  owing  to  the  persist- 
ing activity  of  the  centre  and  this  continues  until,  the  blood  becoming 
less  venous,  the  stimulus  becomes  weaker  and  the  cells  sink  again  into 
their  former  torpor,  to  be  again  resuscitated  by  the  increasing  venosity 
of  the  blood.  Loewy  has  examined  with  particular  care  the  condition 
of  the  respiratory  centre,  and  found  that  much  larger  quantities  of  car- 
bonic acid  than  usual  were  required  to  increase  the  volume  of  the  re- 
spired air  a  given  degree.  His  results  may  indicate  that  the  power  of 
sending  out  impulses  as  well  as  of  receiving  them  is  lessened  by  mor- 
phine, while  the  narcotics  of  the  methane  series  may  perhaps  lessen 
the  receptivity  of  the  centre  without  lessening  its  power  to  emit 
impulses. 

After  large  doses  the  respiration   becomes  gradually  slower  and 


FIG.  18. 


r\ 


Cheyne-Stokes  respiration  in  opium  poisoning.    The  up  strokes  denote  inspiration.    ( After  FILEHNE.  ) 

weaker,  and  often  loses  its  periodic  character.  Even  after  conscious- 
ness fails  to  be  aroused  by  the  most  powerful  shocks,  some  influence 
may  be  exerted  on  the  respiratory  centre.  Thus  the  sudden  application 
of  cold  water  may  cause  several  deep  respirations,  although  it  fails  to 
dispel  the  stupor,  but  the  respiration  finally  fails  to  react  to  these  ap- 
plications and  soon  afterwards  ceases. 


OPIUM' SERIES.  213 

the  action  of  morphine  on  the  central  nervous  system, 
it  produces  great  depression  which  is  especially  marked  in  the  psy- 
chical functions,  but  spreads  over  the  lower  parts  of  the  nervous  axis 
and  involves  sooner  or  later  the  respiratory  centre.  This  depression 
does  not  seem  to  affect  so  much  the  motor  areas  as  the  powers  of  the 
will  and  ftfAQnflfln.  In  mammals  the  failure  of  the  respiration  closes  tKe 
course  of  the  intoxication^  buT  in  the  cold-blooded  animals  a  further 
development  of  excessive  reflex  irritability  follows  which  may  pass 
into  tonic  convulsions.  Even  in  the  higher  animals  and  man  some 
indication  of  this  action  on  the  cord  may  occur,  and  in  the  feline  group 
this  stimulation  involves  not  only  the  cord,  but  also  the  motor  areas 
of  the  brain  apparently. 

Morphine  has  little  direct  action  on  the  Circulation.  The  heart  is 
often  slightly  accelerated  at  first,  perhaps  from  the  slight  nausea. 
The  frog's  heart  is  rendered  slow  and  weak  by  very  large  quantities  of 
morphine. 

The  blood-pressure  remains  high  and  the  peripheral  arteries  in 
general  show  no  change  of  calibre,  with  the  exception  of  those  of  the 
skin,  especially  of  the  head  and  neck,  which  are  dilated,  rendering  the 
face  flushed  and  hot ;  as  asphyxia  comes  on  the  flush  becomes  more 
dusky  and  cyanotic,  but  the  vessels  remain  dilated,  so  that  the  face  is 
of  a  bloated,  purple  color.  The  dilatation  of  these  vessels  has  little  in- 
fluence on  the  general  pressure.  It  arises  from  some  obscure  central 
action,  but  it  is  unknown  whether  this  is  of  the  nature  of  stimulation 
or  of  depression.  The  dilatation  of  the  superficial  vessels  causes  a  sense 
of  warmth  in  the  skin,  which  is  occasionally  followed  by  itching  and 
discomfort.  It  may  account  in  part  for  the  increased  perspiration  often 
observed,  although  this  is  doubtless  contributed  to  by  other  factors. 
As  asphyxia  advances,  the  pulse  may  become  slow,  while  the  blood- 
pressure  varies,  either  rising  from  the  asphyxial  activity  of  the  vaso- 
motor  centre  or  falling  from  the  slowness  of  the  heart.  These  effects 
are  entirely  absent  if  the  blood  be  sufficiently  aerated  by  artificial  res- 
piration, and  are,  therefore,  to  be  regarded  as  indirect  results  of  the 
action  on  the  respiratory  centre. 

The  selective  action  of  morphine  is  thus  excellently  illustrated  in  its 
effects  on  the  medulla  oblongata,  for  the  respiratory  centre  is  paralyzed 
before  the  centres  for  cardiac  inhibition  and  vaso-constriction  are 
affected  to  any  marked  extent. 

The  peripheral  Muscles  and  Nerves  are  also  unaffected  by  morphine 
in  any  except  overwhelming  doses.  Even  when  directly  applied  to 
the  nerve  it  has  but  little  effect  on  the  irritability  (Waller).  When  mor- 
phine is  injected  subcutaneously  in  the  frog  in  large  quantities,  it 
lessens  the  power  of  the  end-organs  to  transmit  impulses,  but  no  such 
effect  is  noted  in  mammals.  It  is  often  stated  that  the  sensory  termi- 
nations are  paralyzed  by  morphine,  and  solutions  are  therefore  injected 
into  the  seat  of  pain,  or  liniments  are  rubbed  into  the  skin  over  it,  but 
as  a  matter  of  fact,  morphine  seems  entirely  devoid  of  any  such  local 


214  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

action.  The  sensibility  of  the  skin  is  lowered  by  an  injection,  it  is 
true,  but  no  more  so  at  the  point  of  application  than  in  other  parts  of 
the  body,  so  that  the  action  appears  to  be  central. 

The  Pupil  undergoes  characteristic  changes  in  morphine  poisoning. 
In  the  great  majority  of  cases  in  man,  the  pupil  is  contracted  to  pin- 
point, dimensions  until  just  before  the  final  asphyxia,  when  it  dilates 
widely.  In  some  animals,  such  as  the  dog  and  rabbit,  the  same  effects 
are  seen,  while  in  birds  the  pupil  remains  unaffected,  and  in  animals  in 
which  morphine  causes  movement  and  excitement,  it  is  dilated  widely. 
The  action  is  undoubtedly  central,  and  not  due  to  any  local  changes  in 
the  eye.  A  number  of  other  drugs  produce  equally  marked  contrac- 
tion of  the  pupil,  but  these  have  the  same  action  when  dropped  into 
the  conjunct! val  sac,  while  morphine  has  no  effect  when  applied  in 
this  way ;  atropine  applied  to  the  conjunctiva  at  once  removes  the 
myosis  produced  by  morphine.  The  terminal  dilatation  seen  in  man 
is  not  due  to  any  direct  action  of  the  poison,  but  is  a  result  of  the 
general  asphyxia. 

As  a  general  rule  the  Secretory  Glands  seem  to  be  rendered  less  ac- 
jive  than  usual  by  morphine.  When  it  produces  nausea,  however,  it 
may  increase  the  saliva  and  the  mucus,  but  these  are  the  usual  accom- 
paniments of  this  condition  and  cannot  be  considered  due  to  any  special 
action  of  the  poison.  The  sweat  glands  are  exceptions  to  the  general 
rule,  however,  for  slight  perspiration  is  generally  observed  from  the 
therapeutic  action,  and  profuse  perspiration  is  seen  before  death  in  some 
cases  in  man  from  the  effects  of  the  asphyxia.  The  urine  does  not 
generally  show  any  distinct  alteration  after  morphine  in  man,  but 
there  is  not  infrequently  retention  in  the  bladder  because  the  sphincter 
reflex  is  absent. 

The  Alimentary  Canal  manifests  some  distinct  changes  under  mor- 
phine, and  although  these  have  been  the  subject  of  numerous  researches 
no  satisfactory  explanation  has  as  yet  been  vouchsafed.  In  the  human 
subject  its  injection  is  occasionally  followed  by  some  nausea,  which  is 
much  more  frequently  present,  however,  during  recovery  from  the 
drug.  In  the  dog  and  cat  nausea  and  vomiting  are  almost  invariable 
sequelae  of  its  application  in  any  form,  and  from  the  rapidity  with 
which  they  follow  its  subcutaneous  injection  would  seem  to  be  due  to 
its  acting  on  the  medullary  centre.  Small  quantities  of  opium  or 
morphine  lessen  the  sensation  of  hunger  in  the  human  subject,  but  this 
is  probably  to  be  attributed  to  central  action  rather  than  to  any  effects 
on  the  stomach.  Batelli  states  that  the  gastric  movements  in  animals 
are  first  increased  and  then  retarded  by  morphine,  and  Riegel  states 
that  in  man  and  the  dog  the  gastric  secretion  is  generally  retarded  at 
first  but  is  subsequently  increased  to  a  considerable  extent.  This  oc- 
curs whether  the  drug  be  administered  by  the  mouth  or  hypodermically 
and  is  therefore  due  to  some  change  induced  by  it  after  absorption. 
The  rate  of  absorption  in  the  stomach  and  bowel  appears  to  be  un- 
changed by  morphine. 


OPIUM  SERIES.  215 

The  effects  on  the  intestine  vary  with  the  dose  injected  as  well  as  with 
the  species  of  animal.  Very  large  quantities  cause  violent  peristalsis 
and  repeated  evacuation  of  the  bowel  in  the  dog,  cat,  and  according  to 
some  authors,  the  rabbit,  while  small  doses,  on  the  other  hand,  are 
followed  by  lessened  peristalsis  and  constipation  in  man  and  in  most 
animals.  Even  in  poisoning  in  man,  the  purgative  effect  is  not  ob- 
served, and  jopium  and  morphine  are  very  extensively  used  in  thera- 
peutics to  quiet  the  movements  of  the  bowel.  Two  explanations  of 
this  action  have  been  offered,  the  first  that  moderate  quantities  of  mor- 
phine stimulate  the  centre  in  the  cord  inhibiting  the  intestinal  move- 
ments, while  larger  doses  paralyze  this  centre  and  thus  allow  the  bowel 
to  contract  more  powerfully  than  usual  (Nothnagel),  the  second  that 
the  central  nervous  system  is  not  concerned  in  the  sedative  effects, 
which  are  attributed  to  morphine  depressing  the  local  mechanism  in 
the  intestinal  wall.  Neither  theory  is  wholly  satisfactory,  and  some 
writers  are,  therefore,  inclined  to  believe  that  the  action  is  partly  cen- 
tral on  the  spinal  cord  and  partly  peripheral  on  the  bowel  wall.  It  is 
to  be  remarked  that  morphine  is  excreted  by  the  intestinal  epithelium 
and  that  this  may  have  some  connection  with  the  excessive  peristalsis. 

It  seems  more  probable  that  the  effects  are  peripheral  than  that 
they  are  central,  for  none  of  the  other  numerous  drugs  which  act 
on  the  spinal  cord  possesses  this  curious  action  on  the  intestinal 
movements. 

Morphine  frequently  causes  a  slight  fall  in  the  Temperature,  which 
may  be  explained  by  the  less  active  movements  and  the  dilatation  of 
the  cutaneous  vessels ;  sometimes  a  slight  preliminary  rise  in  the  tem- 
perature has  been  seen  in  man.  It  is  found  that  animals  under  mor- 
phine react  less  to  an  increase  in  the  surrounding  temperature  than 
unpoisoned  ones ;  i.  e.,  a  normal  animal  exposed  to  a  high  temperature 
takes  measures  to  prevent  its  internal  temperature  from  rising  above 
the  normal,  while,  under  morphine,  these  measures  are  less  effective, 
and  the  temperature  rises  more  rapidly  and  to  a  greater  height ;  this 
indicates  that  the  temperature  centre  in  the  brain  is  rendered  less 
sensitive. 

Metabolism.  —  The  excretion  of  carbonic  acid  is  lessened  during  the 
depression  stage,  while  in  those  animals  in  which  excitement  is  pro- 
duced, it  may  be  considerably  augmented  from  the  increased  muscular 
movement.  The  imperfect  respiration  leads  to  an  increase  in  the  lactic 
acid  of  the  blood  and  urine  and  to  the  disappearance  of  glycogen  from 
the  liver.  Sugar  may  appear  in  the  urine  from  the  same  cause  (Araki). 

Excretion. — Morphine  is  excreted  mainly  by  the  digestive  tract,  in  the 
saliva,  stomach  and  bowel,  and  is  therefore  found  in  large  quantities  in 
the  fa3ces  even  after  hypodermic  injection.  Traces  of  it  occur  also  in 
the  urine  after  large  doses.  It  appears  in  the  stomach  very  soon  after 
injection,  a  weak  reaction  occurring  after  2J  minutes  according  to  Alt, 
but  after  about  an  hour  no  further  excretion  into  the  stomach  has  been 
shown  to  occur,  although  its  narcotic  action  persists  much  longer.  A 


216  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

certain  amount  of  the  morphine  undergoes  partial  oxidation  in  the 
tissues,  and  some  oxidation  products  have  been  said  to  occur  in  the 
urine. 

Tolerance. — The  continued  use  of  morphine  or  opium  leads  to  a  con- 
dition of  tolerance  in  which  enormous  doses  of  the  drug  are  necessary 
to  elicit  any  effect.  Faust  has  succeeded  in  producing  a  similar  state  in 
dogs,  and  finds  that  much  more  morphine  is  oxidized  in  the  tissues  in 
this  condition  than  in  untreated  animals ;  for  when  a  normal  dog  re- 
ceived an  injection  of  morphine,  over  60  per  cent,  of  the  amount  in- 
jected could  be  recovered  from  the  stools,  while  when  a  much  larger 
quantity  was  injected  into  a  tolerant  animal,  none  whatever  was  found 
in  the  excreta.  It  does  not  follow  that  the  absence  of  symptoms  from 
large  doses  in  morphinists  is  due  wholly  to  the  poison  being  oxidized 
before  it  can  reach  the  brain,  for  Cloetta  was  able  to  isolate  large 
quantities  from  the  tissues  of  animals  in  which  tolerance  had  been 
established.  It  is  rather  to  be  inferred  that  the  nerve  cells  become 
habituated  to  its  presence  in  the  blood,  and  cease  to  react  so  strongly 
as  in  normal  individuals,  and  that  in  addition  the  tissues  acquire  a 
greater  power  of  oxidizing  morphine  under  these  circumstances.  The 
attempt  to  find  "  antimorphine  serum  "  has  proved  fruitless. 

Codeine  resembles  morphine  in  the  general  features  of  its  action, 
although  it  is  much  less  poisonous.  It  depresses  the  brain,  and 
causes  an  exaltation  of  the  activity  of  the  lower  parts  of  the  cen- 
tral nervous  system.  Its  depressant  action  is  not  so  powerful  nor  so 
enduring  as  that  of  morphine,  however,  while  the  stimulation  is  more 
evident  and  involves  not  only  the  cord,  but  also  the  medulla  oblon- 
gata  and  lower  parts  of  the  brain.  As  has  been  mentioned  already, 
morphine  also  stimulates  rather  than  depresses  the  brain  in  the 
feline  class,  but  with  codeine  this  is  true  also  for  the  dog  and  to  a 
less  extent  for  man.  In  the  latter  small  quantities  of  codeine  produce 
sleep  but  this  is  not  so  deep  and  restful  as  that  which  follows  the 
administration  of  morphine,  and  the  patient  is  liable  to  be  awakened 
by  slight  noises,  and  is  restless  and  often  unrefreshed  when  he  awakens. 
Somewhat  larger  quantities,  instead  of  inducing  deeper  sleep,  increase 
the  restlessness  and  cause  a  considerable  exaggeration  in 'the  reflex  ex- 
citability. The  respiration  is  not  so  much  slowed  as  after  morphine, 
and,  according  to  Winternitz,  the  excitability  of  the  centre  is  prac- 
tically unchanged,  while  morphine  reduces  it  very  considerably.  The 
pupil  is  slightly  contracted  during  the  codeine  sleep,  but  dilates  when 
the  excitement  stage  follows.  Codeine  does  not  seem  to  produce  so 
great  constipation  as  morphine,  and  in  animals  often  causes  purging 
and  diarrhoea.  It  is  excreted  in  the  urine  mainly,  and  prolonged  ad- 
ministration fails  to  induce  tolerance  or  to  promote  its  destruction  in 
the  tissues  (Bouma). 

Codeine  is  methylmorphine,  and  a  nuniber  of  similar  compounds  have  been 
formed  artificially,  such  as  ethylmorphine  and  amylmorphine.  Two  of  these, 
ethylmorphine  (Dionine)  and  benzylmorphine  (Peronine)  have  recently  been 
introduced  into  therapeutics,  but  appear  to  possess  no  advantages  over  codeine. 


OPIUM  SERIES.  217 

Oxydimorphine  (C?4H36"N"2O6)  has  been  believed  to  be  present  in  the  urine 
after  the  administration  of  morphine.  It  has  also  been  found  in  opium  by 
some  investigators  and  has  a  very  weak  narcotic  action  resembling  that  of 
morphine.  Marme  supposed  that  the  symptoms  seen  after  the  abrupt  with- 
drawal of  morphine  in  cases  of  opium  habit  were  due  to  this  oxydimorphine 
remaining  in  the  tissues,  but  this  has  not  been  confirmed. 

Heroine  is  an  artificial  alkaloid  formed  from  morphine  by  substituting 
acetyl  for  its  two  hydro xy Is,  and  has  attracted  some  attention  recently 
through  its  being  advocated  as  a  respiratory  sedative  in  cough.  It  appears  to 
resemble  morphine  in  its  general  effects,  but  is  said  to  act  more  strongly  on 
the  respiration  and  less  on  the  cerebral  functions.  Thus  the  respiration  is 
rendered  slower  with  less  mental  depression  than  would  accompany  an 
equal  change  elicited  by  morphine.  According  to  the  advocates  of  heroine, 
the  slowness  of  the  breathing  is  in  part  compensated  for  by  its  greater 
depth,  so  that  the  actual  diminution  of  the  air  inspired  is  not  proportional  to 
the  decrease  in  the  number  of  the  movements  ;  but  this  has  been  disputed 
and  is  certainly  not  invariably  true,  particularly  in  man.  On  the  whole  the 
evidence  of  experimental  and  clinical  observers  seems  to  indicate  that  heroine 
deserves  a  place  between  morphine  and  codeine. 

Papaverine  stands  midway  between  codeine  and  morphine  in  its  action  on 
the  central  nervous  system,  but  is  a  comparatively  weak  poison.  Even  in 
large  quantities  it  has  not  the  soporific  action  of  morphine,  nor  does  it 
produce  the  same  degree  of  excitement  as  codeine.  Comparatively  small 
quantities  are  followed  by  sleep,  but  this  does  not  become  deeper  as  the  dose 
is  increased.  On  the  contrary,  the  reflex  excitability  is  augmented,  and 
after  very  large  quantities  some  tetanic  spasm  may  be  elicited,  but  this  seems 
to  be  of  spinal  origin  entirely,  while  that  produced  by  codeine  points  rather 
to  an  affection  of  the  lower  part  of  the  brain.  Papaverine  has  more 
tendency  to  slow  the  heart  rhythm  than  either  morphine  or  codeine  ;  it 
apparently  acts  directly  on  the  heart  muscle  and  not  through  the  regulating 
centres.  The  blood-pressure  is,  however,  little  affected  by  ordinary  quantities. 

Narcotine  resembles  codeine  rather  than  morphine,  but  has  even  less 
depressant  action,  especially  in  mammals.  In  the  frog  a  short  stage  of 
depression  is  elicited,  but  this  soon  gives  place  to  strychnine-like  exaggera- 
tion of  the  reflex  excitability.  In  mammals  there  may  be  but  little  ap- 
pearance of  depression,  the  injection  being  followed  by  a  condition  of  ex- 
citement immediately — restlessness  and  tremors  with  increased  reflexes, 
which  eventually  lead  to  convulsions,  during  which  the  animal  generally 
succumbs  exactly  as  in  strychnine  poisoning.  The  pulse  is  considerably 
slower  after  narcotine  injection  from  a  direct  action  of  the  drug  on  the  heart. 
Narcotine  is  a  very  much  less  poisonous  body  than  either  morphine  or 
codeine,  and  very  large  quantities  have  been  administered  repeatedly  with 
little  or  no  narcotic  effect.  It  is  a  compound  of  hydrocotarnine,  another 
opium  alkaloid,  with  meconin.  Hydrocotarnine  apparently  acts  very  much 
in  the  same  way  as  narcotine,  but  produces  even  less  depression. 

Narceine  has  attained  a  certain  reputation  owing  to  the  statement  of  Cl. 
Bernard  that  it  is  the  most  powerful  narcotic  of  all  the  opium  alkaloids. 
There  seems,  however,  to  be  no  doubt  that  the  preparation  he  used  was  very 
impure,  and  that  narceine  itself  has  little  or  no  action  of  any  kind.  It  is 
exceedingly  insoluble  in  water,  and  its  salts  are  broken  up  in  aqueous 
solution,  so  that  it  is  probably  absorbed  very  slowly  and  imperfectly. 

Thebaine  seems  to  have  practically  no  depressant  action.  It  sometimes 
produces  some  heaviness  and  confusion  in  man,  but  this  is  accompanied  by 
symptoms  exactly  resembling  those  described  under  strychnine,  and  it  may 
therefore  be  considered  as  belonging  to  the  latter  series  rather  than  to  that 
of  morphine  ;  it  is  very  much  less  active  than  strychnine,  however.  Thebaine 
seems  to  differ  from  morphine  also  in  its  effects  on  the  bowel,  for  Vamossy 
finds  that  it  increases  peristalsis  instead  of  allaying  the  irritability.  Lauda- 
nine  seems  to  resemble  thebaine  very  closely  in  its  effects. 


218  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

The  other  alkaloids  occur  in  very  minute  quantities  in  opium  and  possess 
no  great  interest  from  the  therapeutic  point  of  view.  Very  little  has  been 
done  to  elucidate  their  pharmacological  action,  but  those  which  have  been 
examined  seem  to  produce  effects  resembling  those  of  the  better  known  mem- 
bers of  the  group.  There  are  some  exceptions  to  this  rule,  however,  for  in 
the  effects  of  Cryptopine  and  Protopine  some  features  appear  which  seem  to 
be  without  analogue  in  the  action  of  morphine  and  codeine.  In  frogs,  small 
doses  produce  a  narcotic  condition  similar  to  that  following  the  injection  of 
morphine,  but  the  reflex  irritability  does  not  show  the  same  exaggeration 
afterwards  ;  larger  quantities  cause  complete  paralysis  of  the  whole  central 
nervous  system.  At  the  same  time  a  very  marked  action  appears  in  the 
striated  muscles,  the  contraction  of  which  is  altered  in  a  perfectly  character- 
istic manner  ;  if  a  tetanizing  series  of  electric  shocks  be  passed  through  a 
muscle  poisoned  with  these  drugs,  no  real  tetanus,  but  a  series  of  rapid  con- 
tractions and  relaxations  is  produced.  The  ends  of  the  motor  nerves  are  also 
said  to  be  partially  paralyzed.  In  mammals,  no  depression  occurs  but  rest- 
lessness and  eventually  convulsions,  which  do  not  seem  to  be  of  spinal  ori- 
gin but  rather  suggest  a  stimulation  of  the  cerebrum  and  midbrain.  The 
heart  is  slow  and  weak,  and  some  depression  of  the  vaso-motor  centres  is 
caused  by  large  quantities  of  the  poisons.  The  respiration  does  not  seem  to 
be  depressed,  but  rather  to  be  accelerated,  save  by  the  largest  doses. 
They  paralyze  the  terminations  of  the  sensory  nerves  on  local  application  in 
the  same  way  as  will  be  described  under  cocaine.  The  action  of  these  two 
alkaloids  on  muscle  and  on  the  heart  would  seem  to  separate  them  off 
entirely  from  the  other  opium  alkaloids,  although  it  is  not  impossible  that 
these  are  merely  further  developments  of  the  heart  action  noted  after  nar- 
cotine  and  papaverine. 

With  the  exception  of  cryptopine  and  protopine  the  alkaloids  of 
opium  form  a  series,  of  which  morphine  is  one,  thebaine  the  other 
extremity.  In  morphine  the  narcotic  action  is  the  most  striking  fea- 
ture, but  as  the  successive  members  are  taken  up,  this  effect  becomes 
less  marked  than  the  reflex  stimulation,  until  in  thebaine  practically 
no  depression  can  be  made  out,  and  the  symptoms  resemble  those  of 
strychnine  exactly.  Some  of  these  alkaloids,  however,  differ  in  type 
somewhat  from  both  morphine  and  thebaine,  because  the  brain  itself 
seems  the  seat  of  stimulation,  and  the  convulsions  partake  more  of 
the  character  of  those  produced  by  cocaine  and  atropine  than  of  those 
of  strychnine.  Morphine  itself  possesses  this  action  in  the  cat,  so 
that  these  alkaloids  do  not  in  reality  depart  from  the  general  type  so 
completely  as  might  at  first  appear.  The  more  important  members  of 
the  group  may,  therefore,  be  arranged  in  the  following  order,  the  most 
depressant  standing  first  and  the  most  stimulant  last. 

Morphine  (oxydimorphine). 

Papaverine. 

Codeine. 

Narcotine. 

Thebaine. 

(Strychnine.) 

In  man  morphine  is  much  the  most  dangerous  of  the  opium  alka- 
loids, because  death  is  produced  in  the  narcotic  stage  through  asphyxia. 
In  most  animals,  however,  thebaine,  codeine,  and  laudanine  are  more 
toxic,  because  the  failure  of  the  respiration  does  not  occur  in  the  stage 
of  depression,  but  during  the  convulsions. 


OPIUM  SERIES.  219 

Opium  itself  contains  besides  the  alkaloids  already  discussed,  various 
acids  with  which  they  are  in  combination,  meconic,  lactic  and  sul- 
phuric acid,  but  none  of  these  possess  any  action  of  importance.  Along 
with  these  are  found  gums,  sugars,  albumins,  wax,  and  the  other  com- 
mon constituents  of  plant  juices,  but  these  merely  tend  to  delay  the 
absorption  of  the  active  constituents,  and  cannot  be  said  to  play  any 
part  in  the  effects  of  opium.  Of  the  alkaloids,  morphine  is  present 
in  greatest  abundance,  and  is  also  the  most  powerful  in  its  effects. 
The  action  of  opium,  therefore,  is  practically  identical  with  that  of 
morphine,  except  that  the  latter  is  absorbed  more  rapidly  when  pure 
than  when  mixed  with  the  numerous  inactive  substances  of  the  crude 
drug.  Opium  acts  much  more  slowly  than  morphine,  and  seems  to 
produce  more  marked  effect  on  the  intestine  in  which  it  remains  for  a 
longer  time.  It  is  also  said  to  cause  less  nausea,  although  this  is  dis- 
puted. 

U.  S.  P.  PREPARATIONS. 

OPIUM,  the  dried  milky  exudation  obtained  by  incising  the  unripe  cap- 
sules of  Papaver  somniferum,  yields  when  moist  not  less  than  9  per  cent,  of 
crystallized  morphine. 

OPII  PULVIS,  dried  and  powdered  opium,  yielding  12  per  cent,  of  crystallized 
morphine.  Dose,  0.02-0.1  G.  Q-l£  grs.). 

Opium  Deodoratum,  opium  deprived  of  its  odorous  principles  and  of  any  other 
bodies  soluble  in  ether  ;  sugar  of  milk  is  added  to  make  up  the  weight  to  that 
of  the  original.  Dose,  0.02-0.1  G.  (£-lJ  grs.). 

Opium  Granulatum,  a  coarse  powder  containing  12  per  cent,  of  morphine. 
Dose,  0.02-0.1  G.  (i-l£  grs.). 

EXTRACTUM  OPII,  the  dried  aqueous  extract,  contains  20  per  cent,  of  mor- 
phine. Dose,  0.015-0.06.  G.  (J-l  gr.). 

The  following  preparations  contain  10  per  cent,  of  opium  or  from  1.2  to  1.25 
per  cent,  of  morphine. 

TINCTURA  OPII  (Laudanum).     Dose,  0.3-1  c.c.  (5-15  mins.). 

Tinctura  Opii  Deodorati.     Dose,  0.3-1  c.c.  (5-15  mins.). 

Vinum  Opii,  flavored  with  cinnamon  and  cloves.  Dose,  0.3-1  c.c.  (5-15 
mins.). 

Acetum  Opii  (Black  Drop)  is  formed  by  extracting  opium  powder  with 
dilute  acetic  acid.  Dose,  0.3-1  c.c.  (5-15  mins.). 

PULVIS  IPECACUANHA  ET  OPII  (Dover's  Powder),  10  per  cent,  each  of 
opium  and  ipecac  powders.  Dose,  0.3-1  G.  (5-15  grs.). 

Tinctura  Ipecacuanhse  et  Opii.     Dose,  0.3-1  c.c.  (5-15  mins.). 

Other  preparations  of  opium  generally  weaker  than  the  foregoing  are  : 

PILUL^E  OPII,  each  contains  0.065  G.  (1  gr.)  of  opium  powder  or  0.009  G. 
(^  gr.)  of  morphine. 

Trochisci  Glycyrrhizse  et  Opii,  each  contains  0.005  G.  (TV  gr.)  of  opium. 

TINCTURA  OPII  CAMPHORATA  (Paregoric)  contains  four  parts  of  opium 
per  thousand,  along  with  benzoic  acid,  camphor,  oil  of  anise  and  glycerin. 
Dose,  4-15  c.c.  (1-4  fl.  drs.)  for  an  adult,  0.3-1  c.c.  (5-15  drops)  for  a 
child. 

Mistura  Glycyrrhizse  Composita  (Brown  Mixture)  is  formed  from  liquorice, 
syrup,  acacia,  wine  of  antimony,  spirits  of  nitrous  ether  and  camphorated 
tincture  of  opium,  and  contains  only  about  1  part  of  opium  in  2,000.  Dose, 
15-30  c.c.  (i-1  fl.  oz.). 

Emplastrum  Opii,  opium  plaster,  6  per  cent. 


220  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Alkaloids  : 

MOBPHINA  (C17H19NO3  +  H2O),  colorless  crystals  without  odor  but  with  a 
bitter  taste,  practically  insoluble  in  water  and  only  slightly  soluble  in  alco- 
hol. Dose,  0.005-0.03  G.  (&-$  gr.). 

MORPHINE  HYDROCHLORIDUM. 

MORPHINE  SULPHAS. 

Morphinss  Acetas. 

.  Of  these  salts  the  hydrochlorate  and  sulphate  are  the  most  important,  as 
the  acetate  tends  to  decompose  on  keeping.  The  hydrochlorate  and  sulphate 
are  soluble  in  about  21-24  parts  of  water,  less  so  in  alcohol.  They  form 
white,  silky  crystals  with  a  bitter  taste.  Dose,  0.005-0.03  G.  (TV-?  gr.). 

Pulvis  Morphinse  Compositus  (Tully's  Powder)  is  a  mixture  of  liquorice 
powder,  camphor  and  morphine  sulphate,  in  which  the  latter  is  contained  to 
the  amount  of  If  per  cent.  Dose,  0.3-1  G.  (5-15  grs.). 

CODEINA  (C18H21NO3  -|-  H2O),  white  or  nearly  transparent  crystals  with  a 
faintly  bitter  taste,  soluble  in  80  parts  of  water  and  in  3  parts  of  alcohol. 
Dose,  0.015-0.12  G.  (£-2  grs.). 

CODEINE  PHOSPHAS. 

CODEINJE  SULPHAS. 

These  salts  of  codeine  form  white  needle-shaped  crystals  with  a  bitter  taste. 
The  phosphate  is  soluble  in  about  2  parts  of  water,  the  sulphate  in  30  parts. 
Dose,  0.03G.  (J  gr.). 

B.  P.  PREPARATIONS. 

OPIUM,  the  juice  obtained  by  incision  from  the  unripe  capsules  of  Papaver 
somniferum,  inspissated  by  spontaneous  evaporation.  When  dried  it  con- 
tains 91-101  per  cent,  of  anhydrous  morphine,  and  it  is  therefore  weaker 
than  the  corresponding  preparation  of  the  U.  S.  P.  Dose,  |-2  gvs. 

EXTRACTUM  OPII  contains  20  per  cent,  of  morphine.     Dose,  J-l  gr. 

Extractum  Opii  Liquidum  contains  £  per  cent,  of  morphine  (£  gr.  in  110 
mins.).  Dose,  5-30  mins. 

TINCTURA  OPII,  Laudanum,  contains  f  per  cent,  of  morphine,  or  about  1 
gr.  of  opium  in  15  mins.  Dose,  5-15  mins.  for  repeated  administration ; 
for  a  single  administration  20-30  mins. 

Tinctura  Opii  Ammoniata  is  formed  of  laudanum,  benzoic  acid,  oil  of  anise 
and  ammonia.  It  contains  about  £  per  cent,  of  morphine  or  nearly  5  grs.  of 
opium  in  the  fluid  oz.  Dose,  |-1  fl.  dr. 

TINCTURA  CAMPHORS  COMPOSITA,  Paregoric  or  Paregoric  Elixir,  re- 
sembles the  foregoing  in  composition  except  that  camphor  is  substituted  for 
ammonia  and  that  the  laudanum  is  reduced  so  that  only  one  part  of  mor- 
phine is  contained  in  2,000  of  paregoric  or  £  gr.  of  opium  in  each  fl.  dr. 
Dose,  i-1  fl.  dr. 

Pulvis  Opii  Compositus  contains  10  per  cent,  of  opium  along  with  pepper, 
ginger,  caraway  and  tragacanth.  Dose,  2-10  grs. 

PULVIS  IPECACUANHA  COMPOSITUS,  Dover's  Powder,  contain  10  per  cent, 
each  of  opium  and  ipecacuanha  in  powder.  Dose,  5—15  grs. 

PULVIS  KINO  COMPOSITUS  contains  5  per  cent,  of  opium  along  with  kino 
and  cinnamon.  Dose,  5-20  grs. 

PULVIS  CRET^C  AROMATICUS  CUM  OPIO  contains  2£  per  cent,  of  opium 
along  with  aromatic  chalk  powder.  Dose,  10-40  grs. 

PILULA  PLUMBI  CUM  OPIO  contains  12  \  per  cent,  of  opium  along  with  lead 
acetate.  Dose,  2-4  grs. 

PILULA  SAPONIS  COMPOSITA,  contains  20  per  cent,  of  opium.    Dose,  2-4  grs. 

Pilula  Ipecacuanhse  cum  Scilla  is  formed  from  Dover's  powder  and  squills, 
and  contains  about  5  per  cent,  of  opium.  Dose,  4-8  grs. 

SUPPOSITORIA  PLUMBI  COMPOSITA,  each  contains  3  grs.  of  lead  acetate 
and  1  gr.  of  opium. 

Linimentum  Opii  (f  per  cent,  of  morphine), 


OPIUM  SERIES.  221 

Emplastrum  Opii  (10  per  cent,  opium). 

Unguentum  Gallse  cum  Opio  contains  1\  per  cent,  of  opium. 

Morphinse  Acetas  (C17H19NO3,C2H4O23H2O),  a  white  crystalline  or  amor- 
phous powder  almost  entirely  soluble  in  2£  parts  of  water  and  in  100  of 
alcohol,  £-£  gr. 

MORPHINE  HYDROCHLORIDUM  (C17H19NO3,HC1,3H2O),  acicular  prisms  of 
a  silky  lustre,  soluble  in  24  parts  of  cold  water,  one  part  of  boiling  water  or 
50  of  alcohol.  Dose  £-£  gr. 

Morphinse  Tartras  ((C17H19NO3)2C4H6O6,3H2O),  a  white  powder  consisting 
of  fine  nodular  tufts  of  acicular  crystals,  soluble  in  11  parts  of  cold  water, 
insoluble  in  alcohol.  Dose,  J— £  gr. 

Liquor  Morphinse  Acetatis,  1  per  cent.,  10-60  mins. 

LIQUOR  MORPHINE  HYDROCHLORIDI,  1  per  cent.,  10-60  mins. 

Liquor  Morphinse  Tartratis,  1  per  cent.,  10-60  mins. 

INJECTIO  MORPHINSE  HYPODERMICA  contains  1  per  cent,  of  the  tartrate. 
Dose  by  subcutaneous  injection,  2-5  mins. 

SUPPOSITORIA  MORPHINSE,  each  contains  £  gr.  of  morphine  hydrochloride. 

TROCHISCUS  MORPHINE,  each  contains  ^  gr.  of  morphine  hydrochloride. 

Trochiscus  Morphinse.  et  Ipecacuanhas,  each  contains  ^  gr-  of  morphine  hy- 
drochloride with  7*2  gr.  of  ipecacuanha  root. 

Tinctura  Chloroformi  et  Morphinse  Composita  corresponds  to  the  patented 
chlorodyne  and  contains  1  per  cent,  of  morphine  hydrochloride,  along  with 
chloroform,  prussic  acid,  capsicum,  cannabis  indica,  oil  of  peppermint  and 
glycerin.  Dose,  5-15  mins. 

CODEINA  (C17H18(CH3)NO3,H2O),  colorless  crystals  soluble  in  80  parts  of 
water,  readily  soluble  in  alcohol  and  ether.  Dose,  \-2  grs. 

Codeinse  Phosphas  ((C17H18(CH3)NO3,H3PO4)23H2O),  white  crystals  with  a 
slightly  bitter  taste,  soluble  in  4  parts  of  water,  much  less  soluble  in  alcohol. 
Dose,  ^-2  grs. 

SYRUPUS  CODEINE,  one  fluid  drachm  contains  ^  gr.  of  codeine  phosphate. 
Dose,  $-2  fl.  drs. 

Papaveris  Capsulse,  the  nearly  ripe  dried  fruits  of  Papaver  somniferum, 
contain  a  small  percentage  of  morphine,  but  are  entirely  superfluous  in 
therapeutics. 

Therapeutic  Uses.  —  Opium  is  one  of  the  most  important  and  most 
extensively  used  drugs  in  the  pharmacopoeias  at  the  present  day  as  in 
the  past.  Of  late  years  the  crude  drug  has  been  largely  replaced  by 
morphine,  but  the  action  is  the  same,  and  although  morphine  is  pref- 
erable in  most  cases,  opium  is  still  specially  indicated  for  certain  pur- 
poses. In  almost  any  disease,  conditions  which  are  favorably  influenced 
by  morphine  may  present  themselves,  and  these  conditions  alone  can 
be  discussed  here. 

Pain.  —  As  has  been  repeatedly  mentioned,  opium  or  morphine  has 
a  special  analgesic  action  which  is  not  shared  by  its  modern  rivals  of 
the  methane  series,  and  which  justifies  the  celebrated  dictum  of  Syden- 
ham  that  without  opium  few  would  be  callous  enough  to  practise 
therapeutics.  The  general  statement  may  suffice  that  severe  pain  in- 
dicates opium.  Even  where  the  disease  in  itself  is  one  which  would 
in  ordinary  circumstances  contraindicate  it,  it  must  be  always  taken 
into  consideration  whether  the  relief  of  the  pain  and  its  attendant  rest- 
lessness may  not  counterbalance  the  disadvantages  of  the  narcotic.  At 
the  same  time  the  danger  of  inducing  the  craving  for  morphine  cannot 
be  forgotten,  for  the  use  of  morphine  to  subdue  pain  is  perhaps  the 


222  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

most  fruitful  cause  of  the  habit.  It  is  often  found  that  comparatively 
small  quantities  of  opium  are  sufficient  to  remove  or  at  any  rate  to 
dull  pain,  but  after  repeated  doses  the  quantity  has  to  be  increased 
owing  to  tolerance  being  attained.  Some  forms  of  pain  are  relieved 
by  the  members  of  the  antipyrine  series,  but  these  are  less  certain 
and  more  limited  in  their  action  than  morphine.  On  the  other  hand 
the^  antipyretics  often  relieve  pain  without  inducing  sleep,  and  in  this 
possess  a  groat  advantage  over  opium  in  the  treatment  of  headache, 
neuralgia  and  similar  conditions. 

\\~    Sleeplessness.  — Opium  was  formerly  the  only  drug  used  to  induce 

*>^sleep,  but  since  the  discovery  of  chloral  and  its  congeners  it  is  used 
less  frequently.  These  fail  entirely  to  replace  it,  however,  where  the 
sleeplessness  is  due  to  pain,  while,  on  the  other  hand,  they  are  more 
efficacious  in  some  conditions  of  excitement.  Not  infrequently  opiumj 
land  chloral  are  prescribed  together  for  this  purpose,  and  the  combi-j 
\nation  acts  more  efficiently  than  either  of  the  drugs  alone.  Each  is, 
of  course,  prescribed  in  considerably  smaller  amount  than  if  adminis- 
tered separately.  Opium  is  less  efficient  than  chloral  when  there  is 
apparently  an  increased  activity  of  the  motor  functions  of  the  brain,  as 
in  wild  delirium  and  mania,  and  sometimes  seems  to  increase  the  excite- 
ment even,  but  this  general  statement  is  subject  to  numerous  excep- 
tions, and  morphine  is  still  largely  used  in  many  such  disorders.  In 
the  true  convulsive  diseases,  such  as  tetanus,  epilepsy  and  chorea, 
chloral  is  preferable.  The  beneficial  effect  of  morphine  in  many  acute 
febrile  conditions  is  undeniable,  and,  as  in  the  case  of  alcohol,  is  due 
to  its  lessening  the  pain  and  discomfort  of  the  patient  and  inducing 
rest.  A  good  deal  of  difference  of  opinion  exists  as  to  the  advisability 
of  administering  opium  or  morphine  in  these  conditions,  and  there  is 
no  question  that  the  routine  treatment  of  fever  by  narcotics  is  to  be 
deprecated ;  but  on  the  other  hand,  the  restlessness  and  discomfort 
may  in  itself  aggravate  the  disease,  and  morphine  is  distinctly  indicated 
under  these  circumstances. 

The  preparations  chiefly  used  to  relieve  pain  and  promote  sleep  are 
the  extracts,  laudanum,  opium  pill,  or  compound  soap  pill,  and  the 
morphine  salts  and  their  solutions.  The  latter  may,  of  course,  be  ad- 

.•  ministered  hypodermically. 
^\]        In  Respiratory  Disorders,  opium  and  morphine  are  largely  used  for 

^"•1-u~:-  effects  on  the  centre.     Where  it  is  desirable  to  lessen  its  irrita- 


bility,  as  for  example  in  excessive  cough  and  dyspnoea,  opium  may 
be  indicated.  On  the  other  hand,  when  there  is  a  profuse  expectora- 
tion, the  irritability  of  the  centre  cannot  be  lowered  without  danger, 
and  opium  is  contraindicated.  Opium  gives  relief  in  cases  of  asthma, 
but  there  is  always  danger  of  inducing  the  habit. 

Opium  is  often  combined  with  expectorants  in  the  treatment  of 
cough,  and  a  large  number  of  suitable  preparations  are  provided  in 
the  pharmacopoeias,  such  as  paregoric,  Dover's  powder  and  other  prepa- 
rations containing  ipecacuanha,  liquorice  mixture,  the  compound  mor- 
phine powder  (U.  S.  P.),  the  ammoniated  tincture,  the  compound 


OPIUM  SERIES.  223 

tincture  of  chloroform  and   morphine,  the  pills  of  ipecacuanha  and 
squill  (B.  P.),  the  lozenges  and  the  codeine  preparations.     .Codeine  is 
often  preferred  to  morphine  in  these  cases,  because  it  reduces  the  ex-  - 
citability  of  the  respiratory  centre  with  less  marked  cerebral  depression,^ 
This  is  also  true  of  the  new  artificial  alkaloids,  heroine  and  dionine, 
which  have  enjoyed  some  popular  reputation  in  late  years.     Impartial 
investigators  of  these  drugs  have  generally  failed   to  obtain   better 
results  from  them  than  from  codeine  and  morphine,  and  further  inves- 
tigation is  required  before  they  can  be  recommended  as  superior  to  the 

/.older  and  unpatented  alkaloids. 

In  Peritonitis  and  Intestinal  Disorders,  opium  is  indicated  doubly  5 

Xftrst,  for  its  general  action  in  allaying  pain  and  restlessness ;  and  secondly, 
for  its  special  action  in  lessening  the  movement  of  the  intestine.  Opium 
is  preferable  to  morphine  for  these  purposes  because  it  lies  longer  in 
the  bowel,  and  therefore  evolves  a  stronger  action  there  than  on  the  rest 
of  the  economy.  In  colic,  especially  lead  colic,  it  often  relieves  the 
pain  without  increasing  the  constipation  and  seems  to  allay  the  spasm 
of  the  bowel  without  stopping  entirely  its  peristalsis.  In  diarrhoea 
opium  may  be  given  to  check  the  excessive  peristalsis,  though  in  the 
severer  forms  of  dysentery  it  generally  fails  to  have  this  effect,  and  in 
septic  purging  is  rather  to  be  avoided.  In  perforation  and  hemor- 
rhage from  the  bowel,  opium  is  the  most  efficient  of  all  remedies,  as  it 
allows  adhesions  or  clots  to  be  formed  by  checking  movements  of  the 
intestine,  which  would  provoke  further  leakage. 

The  B.  P.  offers  a  number  of  preparations  specially  designed  for 
use  in  intestinal  disorders  and  especially  in  diarrhoea,  such  as  the  com- 
pound kino  powder,  the  compound  chalk  powder,  the  lead  and  opium 
pill,  and  the  compound  lead  suppository  and  morphine  suppository. 
Instead  of  these  the  tincture,-  extract  or  other  simple  preparation  may, 

i  of  course,  be  used. 

In  Haemorrhage,  where  the  bleeding  point  cannot  be  reached,  opium 

*  or  morphine  is  most  valuable.  This  is  not  from  any  direct  effect  on 
the  vessels  or  blood,  but  because  itf)allays  the  restlessness  which  follows 
the  loss  of  large  quantities  of  blood  and  thus  allows  the  blood  to  clot 
in  the  ruptured  vessel.  The  same  preparations  are  suitable  here  as  for 
pain. 

In  Vomiting  morphine  is  sometimes  used  in  small  quantities,  but  it 
seems  doubtful  whether  with  any  benefit. 

An  injection  of  10  mg.  (-i  gr.)  of  morphine  often  facilitates  the 
use  of  ether  in  Anaesthesia  and  is  a  routine  practice  in  some  clinics. 

^  In  others  0.3  mg.  hyocine  is  added,  and  very  small  quantities  of  ether 
are  required  afterward. 

Opium  has  been  used  instead  of  quinine  in  Malaria,  and  though  it  can- 

J^not  be  said  to  replace  the  latter,  has  a  distinct  effect  in  some  cases  appar- 
ently.    Of  course,  symptoms  may  arise  in  malaria  as  in  other  diseases  in 
which  opium  is  specially  indicated,  but  apart  from  this,  cases  of  malaria 
of  old  standing  seem  to  be  benefited  by  opium  with  or  without  quinine. 
Opium  or  morphine  has  sometimes  been  used  in  Diabetes  with  good 


> 


224  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

effects ;  for  though  the  glycosuria  seldom  disappears  under  its  use,  it  is 
lessened  in  some  cases  (Kaufmann).  Codeine  has  been  advised  instead 
of  morphine  in  this  disorder,  as  it  is  less  likely  to  cause  constipation 
and  gastric  disturbance. 

Lastly,  opium,  is  used  as  a  Diaphoretic,  and  for  this  purpose  it  is  gen- 
erally combined  with  ipecacuanha  and  prescribed  as  Dover's  powder. 
Although  in  itself  it  has  little  or  no  diaphoretic  action,  ^^um  rnjiy 
augment  the  effects  of  ipecacuanha  through  dilating  the  skin  vessels. 
Opium  and  its  alkaloids  have  no  effect  applied  to  the  skin,  and  the 
plasters,  ointments  and  other  similar  preparations  are  quite  superfluous. 

Codeine  is  much  less  often  used  than  morphine  in  therapeutics.  It 
is  of  comparatively  little  value  in  allaying  pain  or  excitement,  but 
has  been  found  of  benefit  in  the  sleeplessness  of  melancholia.  It  is 
used  not  infrequently  as  a  sedative  in  cough,  and,  as  has  been  stated, 
in  diabetes.  There  seems  less  liability  to  the  formation  of  the  codeine 
habit,  and  it  has  been  suggested  as  a  substitute  for  morphine  in  mor- 
phinornania,  but  has  not  proved  efficient  in  this  condition. 

Opium  and  morphine  are  contraindicated  in  very  young  children, 
in  whom  even  minute  quantities  often  produce  the  most  alarming 
symptoms  of  poisoning.  Even  one  drop  of  laudanum  is  said  to  have 
been  fatal  to  a  child  under  one  year  of  age.  In  great  weakness, 
especially  in  cases  where  the  respiration  is  barely  sufficient  to  aerate 
the  blood,  or  where  profuse  expectoration  is  present,  morphine  has  to 
be  administered  with  the  greatest  care.  In  cerebral  congestion  and 
meningitis  the  opiates  are  generally  contraindicated.  It  must  be  re- 
membered also  that  both  opium  and  morphine  are  liable  to  disturb  the 
digestion  and  to  cause  nausea  and  want  of  appetite,  and  that  these  may 
prevent  their  use  in  cases  in  which  they  would  otherwise  be  suitable. 
In  some  persons  opium  invariably  causes  nausea  and  vomiting,  either 
soon  after  its  administration  or  while  its  effects  are  passing  off.  For 
this  idiosyncrasy  morphine  may  be  substituted  for  opium,  although  this 
is  often  equally  nauseating,  or  chloral  and  bromides  may  be  prescribed 
with  opium  to  prevent  the  unpleasant  after-effects.  Not  infrequently, 
however,  opium  has  to  be  avoided  entirely.  In  all  chronic  painful 
diseases  opium  or  morphine  has  to  be  given  guardedly,  on  account  of 
the  risk  of  the  formation  of  the  opium  habit ;  the  patient  ought  to  be 
kept  in  ignorance  of  the  drug  used  as  far  as  possible,  and  it  should  be 
alternated  with  others.  Of  course,  in  cases  of  incurable,  hopeless  dis- 
ease, where  life  can  only  last  a  comparatively  short  time  and  is  attended 
by  severe  suffering,  this  objection  does  not  hold,  and  it  may  be  neces- 
sary to  administer  morphine  without  stint  and  in  ever-increasing 
quantity. 

Morphine  and  opium  are  often  said  to  be  contraindicated  in  Bright' g 
disease  of  the  kidney.  This  seems  to  be  due  to  the  belief  that  mor- 
phine is  excreted  in  the  urine,  which  has  now  been  shown  to  be  erro- 
neous. There  seems  no  reason  to  believe  that  morphine  is  harmful  in 
these  conditions,  and  in  some  forms  of  uraemia  it  has  even  been  of 
considerable  benefit. 


OPIUM  SERIES.  225 

Acute  Poisoning  with  morphine  or  opium  is  one  of  the  commonest 
forms  of  intoxication,  with  the  exception  of  the  alcoholic.  It  is  often 
difficult  to  diagnose  from  other  forms  of  unconsciousness,  but  the  ex- 
treme contraction  of  the  pupils  give  a  clue,  as  a  general  rule,  and  if 
opium  has  been  used,  the  breath  often  has  the  characteristic  odor. 

The  treatment  is  immediate  evacuation  of  the  stomach,  whether  the 
drug  has  been  taken  by  the  mouth  or  not,  as  even  when  injected  hypo- 
dermically  it  is  excreted  into  the  stomach  and  may  be  reabsorbed. 
Emetics  may  be  employed  for  this  purpose,  but  often  fail  of  effect 
owing  to  the  depression  of  the  medullary  centres,  so  that  where  possible 
a  stomach  tube  ought  to  be  used  in  preference.  The  stomach  should 
be  thoroughly  washed  out  at  intervals,  in  order  to  remove  every 
trace  of  the  drug  as  it  is  excreted.  As  the  respiration  begins  to  fail, 
it  is  to  be  encouraged  by  irritation  of  the  skin,  either  by  dashing  cold 
water  on  it,  by  the  electric  current,  or  by  flipping  it  with  towels. 
The  violent  flagellation  formerly  advocated  with  the  view  of  en- 
couraging the  respiration,  served  also  usually  to  exhaust  the  nervous 
energy  both  of  patient  and  attendant.  When  these  means  fail  to  keep 
up  the  natural  breathing,  it  is  necessary  to  resort  to  artificial  respira- 
tion, either  electrical  or  mechanical,  and  this  ought  to  be  continued  as 
long  as  the  heart  continues  to  beat.  Enormous  doses  of  morphine  and 
opium  have  been  recovered  from  under  this  treatment.  Numerous  drugs 
have  been  advocated  in  acute  morphine  poisoning,  and  of  these  caffeine 
administered  either  hypodermically  or  in  the  form  of  strong  coffee 
by  the  stomach  seems  the  most  satisfactory.  A  long  controversy  has 
been  carried  on  as  to  whether  atropine  is  to  be  considered  an  antidote 
to  morphine  and  used  in  these  cases.  It  is  a  stimulant  to  the  medullary 
centres,  and  may,  therefore,  be  used  in  small  quantities  ;  but  large  quan- 
tities, such  as  have  been  advised  by  some  authorities,  are  undoubtedly 
harmful,  as  atropine  itself  paralyzes  the  respiration  when  given  in 
sufficient  amount.  Bashford  states  that  the  best  effects  are  to  be  ex- 
pected from  about  1.5  mg.  (-fa  gr.)  of  atropine  and  that  more  than  this 
increases  the  danger  of  respiratory  failure.  In  discussing  this  ques- 
tion too  great  weight  has  been  laid  on  the  results  of  animal  experi- 
ment, which  is  not  convincing  in  this  case,  as  the  effects  of  morphine 
are  so  different  in  man.  Caffeine  seems  certainly  more  indicated  than 
atropine,  for  it  is  scarcely  possible  to  paralyze  the  respiratory  centre 
with  the  former,  which  stimulates  it  equally  strongly.  Alcohol  has 
been  advised  also,  and  as  far  as  its  local  action  is  concerned,  it  may 
increase  the  respiration,  but  its  direct  action  on  the  respiratory  centre 
is  similar  to  that  of  opium.  Of  late  years  permanganate  of  potash  has 
been  advised  in  case  of  morphine  poisoning,  because  the  poison  is  oxi- 
dized by  it.  A  certain  amount  of  poison  in  the  stomach  may  be  de- 
stroyed in  this  way,  but  the  portion  absorbed  is  unaffected  by  the  per- 
manganate, and  the  method  is  less  efficacious  than  the  prompt  and 
repeated  use  of  the  stomach  tube.  The  hypodermic  injection  of  per- 
manganate is,  of  course,  entirely  useless. 

Chronic  Opium  or  Morphine  Poisoning  is  a  not  infrequent  condition, 

15 


226  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

and,  unfortunately,  seems  to  be  increasing  rapidly.  Among  Eastern 
nations,  especially  in  China  and  India,  opium  is  smoked,  and  some  of 
the  morphine  is  carried  over  in  the  smoke  and  absorbed  from  the'  res- 
piratory tract.  This  habit  is  rare  in  European  peoples,  among  whom 
the  drug  is  taken  by  the  mouth,  generally  in  the  form  of  laudanum  or 
of  -~>ills,  or  is  injected  hypodermically  as  morphine  hydrochlorate  or 
sulphate.  Of  the  three  methods  the  first  seems  to  be  the  least  harmful, 
for  in  some  parts  of  China  the  majority  of  the  adult  population  seems 
to  indulge  in  it  without  the  serious  results  which  are  met  with  in  the 
Western  opium-eaters  and  morphinomaniacs.  This  result  may  be  due 
in  part  to  race,  or  to  the  fact  that  the  opium-smoker  never  attains  to 
the  immense  doses  taken  daily  in  the  cases  of  the  habit  met  with  in 
Europe  and  America.  In  the  beginning  the  quantity  used  is  small, 
but  as  tolerance  is  attained,  ever  larger  quantities  are  required  to  pro- 
duce any  effect,  until,  as  De  Quincy  states  in  his  "  Confessions  of  an 
English  Opium-eater,"  320  grains  of  opium  may  be  required  to  stay  the 
craving.  The  effects  are  generally  described  as  stimulant,  but  it  seems 
possible  that  they  consist  rather  in  depression  of  the  sensibility,  by 
which  the  unfortunate  patient  becomes  unconscious  of  the  miseries  of 
his  condition,  and  may  accordingly  be  able  to  perform  his  duties  and 
maintain  appearances  better  than  when  deprived  of  the  poison.  The 
symptoms  of  the  opium  habit  are  exceedingly  indefinite,  and  the  diag- 
nosis is  often  almost  impossible.  The  statements  of  the  patient  ought 
not  to  be  taken  into  consideration,  because  these  unfortunates  seem  to 
have  lost  all  idea  of  honor  and  truthfulness.  As  a  general  rule  they 
are  nervous,  weak  in  character  and  wanting  in  energy,  and  utterly 
unfit  for  work  unless  when  supplied  with  the  drug.  The  pupils  are 
often  contracted,  the  heart  sometimes  irregular,  and  tremors  and  un- 
steadiness in  walking  may  be  apparent.  The  appetite  is  bad  and  a 
considerable  loss  in  weight  occurs,  and  the  movements  of  the  bowels 
are  irregular,  constipation  alternating  with  diarrhoea.  Eventually 
melancholia  and  dementia  may  follow  the  prolonged  use  of  opium, 
and  especially  of  morphine.  Some  continue  the  habit  for  many  years, 
however,  and  it  would  seem  with  comparative  immunity.  If  mor- 
phine is  injected  habitually,  evidence  may  be  obtained  from  the  small 
needle  marks  on  the  front  of  the  body,  which  often  give  rise  to  mul- 
tiple abscesses  of  small  size  from  carelessness  in  the  disinfection  of  the 
syringe.  When  other  evidence  fails,  it  may  be  necessary  to  give  a 
moderate  dose  disguised  in  some  unusual  way  and  to  observe  if  it  in- 
duces sleep  ;  in  habitual  users  the  ordinary  dose  will  have  little  or  no 
effect. 

The  treatment  of  chronic  morphine  poisoning  is  not  very  promising. 
The  will  and  self-control  would  seem  completely  paralyzed  in  many 
cases,  and  although  the  patient  wishes  to  be  freed  from  his  enemy,  he 
seems  utterly  unable  to  withstand  the  craving.  The  only  means  of 
treatment  which  promises  success  in  most  cases  is  the  strict  regime  of 
an  asylum  or  retreat,  where  the  patient  is  kept  under  constant  super- 
vision. The  immediate  removal  of  the  drug  often  produces  such  in- 


OPIUM  SERIES.  227 

tense  misery  and  depression  as  to  seem  actually  dangerous ;  but  the 
withdrawal  ought  not  to  be  too  gradual,  and  ought  to  be  complete  after 
two  or  three  weeks  at  the  most.  The  patient  has  to  be  watched  care- 
fully for  long  after  he  has  apparently  recovered,  as  relapses  are  ex- 
ceedingly common. 

The  morphine  habit  has  often  been  combated  by  the  substitution  of 
other  drugs,  such  as  cocaine,  but  the  result  generally  has  been  that  a 
new  and  even  more  dangerous  habit  has  been  substituted  for,  or  often 
merely  grafted  on,  the  original.  Numerous  drugs  have  been  proposed 
for  the  cure  of  morphinomania,  but  none  of  them  seems  to  have  the 
slightest  effect. 

BIBLIOGRAPHY. 

The  literature  of  opium  is  so  immense  that  only  a  few  of  the  more  important  phar- 
macological papers  can  be  mentioned  here. 

CL  Bernard.     Lefons  sur  les  Ansesthesiques  et  sur  P  asphyxia.     Paris,  1875. 

Gscheidlen.  Untersuchungen  aus  dem  physiologischen  Laboratorium  zu  Wurzburg, 
ii.,  p.  1. 

Baxt.     Arch.  f.  Anat.  und  Phys.,  1869,  p.  112. 

Filehne.  Arch.  f.  exp.  Path.  u.  Pharm.,  x.,  p.  442;  xi.,  p.  45.  Pfliiger's  Arch., 
Ixii.,  p.  201. 

Loewy.     Pfliiger' s  Archi v,  xlvii.,  p.  601. 

Araki.     Ztschr.  f.  phys.  Chem.,  xix.,  p.  422. 

Salvioli.     Arch.  f.  Anat.  und  Phys.,  1880,  Supplement,  p.  95. 

Bubnoffu.  Heidenhain.     Pfliiger's  Arch.,  xxvi.,  p.  137. 

v.  Schroeder.     Arch.  f.  exp.  Path.  u.  Pharm.,  xvii.,  p.  96. 

Witkowski.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii.,  p.  247. 

Pohl.     Arch.  f.  exp.  Path.  u. "Pharm.,  xxxiv.,  p.  87. 

AH.     Berl.  klin.  Woch.,  1889,  p.  560. 

Levison.     Diss.  Bonn,  1894.     Berl.  klin.  Woch.,  1894,  p.  891. 

Brunton  u.  Cash.     Beitrage  zur  Physiologic,  C.  Ludwig  gewidmet,  1887,  p.  149. 

Stockmann  and  Dott.  Proc.  Roy.  Soc.  Edinburgh,  1890.  British  Medical  Journal, 
1890,  ii.,  p.  189,  and  1891,  i.,  p.  157. 

Engel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii.,  p.  419.     (Protopine. ) 

RJieiner.     Therap.  Monatsch.,  1889,  p.  393.     (Codeine.) 

Dreser.     Ibid.,  1898,  p.  509. 

Stursberg.     Arch,  de  Pharmacodyn.,  iv.,  p.  325. 

Winternitz.     Pfliiger's  Arch.,  Ixxx.,  p.  344. 

Marshall.     Med.  Chronicle,  April,  1901. 

Riegel.     Ztschr.  f.  klin.  Med.,  xl,  p.  347. 

Holsti.     Ibid.,  xlix.,  p.  1. 

Bashford.     Arch,  internat.  de  Pharmacodyn.,  viii.,  p.  311. 

Faust.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv.,  p.  217. 

Cloetta.     Ibid.,  1.,  p.  453. 

Bouma.     Ibid.,  1.,  p.  353.     (Codeine.) 

Magnus.  Ergebnisse  d.  Physiol.,  i.,  2,  p.  437  (Respiration) ;  ii.,  2,  p.  657  (Intestinal 
Action). 

Kaufmann.   Ztschr.  f.  klin.  Med.,  xlviii.,  p.  260. 

Minor  Drugs  of  the  Opium  S'eries. 

In  some  other  members  of  the  poppy  family  (Papaveracese),  alkaloids  are 
found  which  bear  a  close  resemblance  to  those  of  opium.  There  are  Cheli- 
donine,  «-,  P-andy-Homochelidonine,  Chelerythrine  and  Sanguinarine ;  Protopine 
is  also  found  in  a  number  of  other  papaveraceae.  These  alkaloids  are  met 
with  in  very  small  quantities  in  various  plants,  of  which  Sanguinaria  Cana- 
densis  (Bloodroot)  and  Chelidonium  majus  (Celandine)  are  the  best  known. 

Chelidonine  and  a-homochelidonine  resemble  morphine  in  their  effects  on  the 
central  nervous  system,  but  have  even  less  stimulant  effect.  In  the  frog  no 
secondary  increase  in  the  reflex  irritability  is  produced,  but  in  some  mam- 
mals a  slight  stimulation  of  the  spinal  cord  may  be  caused.  They  have  the 


228  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

same  effect  as  protopine  and  cryptopine  on  the  muscles  and  heart,  and  like 
them  produce  insensibility  of  the  skin  and  cornea  when  applied  locally 
through  paralyzing  the  terminations  of  the  sensory  nerves.  The  heart  is 
slowed,  partly  owing  to  stimulation  of  the  inhibitory  centres  in  the  medulla, 
and  partly  through  direct  action  on  the  cardiac  muscle. 

Sanguinarine  has  very  little  depressant  action,  but  causes  tetanus  and  wild 
excitement,  so  that  as  far  as  its  action  on  the  central  nervous  system  is  con- 
cerned, it  deserves  a  place  between  codeine  and  thebaine  of  the  morphine 
series.  It  possesses  the  same  muscular  action  as  protopine,  however,  and 
the  heart  is  slowed  through  direct  affection  of  the  muscle.  Sanguinarine 
paralyzes  the  peripheral  sensory  endings  when  applied  locally,  but  this 
paralysis  is  preceded  by  a  stage  of  irritation.  It  causes  violent  peristalsis  of 
the  bowel,  and  increases  the  secretion  of  saliva. 

p-homochelidonine  resembles  protopine  and  cryptopine  closely  in  its  effects, 
causing  the  same  stimulation  of  the  lower  parts  of  the  brain  with  very  slight 
effects  on  the  intellectual  powers,  slowing  the  heart  through  its  muscular 
action  and  paralyzing  the  sensory  terminations. 

Chelerythrine  paralyzes  the  central  nervous  system  without  any  prelimi- 
nary increase  in  the  reflex  irritability,  possesses  the  muscular  action  of  pro- 
topine and  cryptopine,  and  first  irritates  and  then  paralyzes  the  sensory 
terminations. 

None  of  these  alkaloids  have  been  used  in  therapeutics,  and  there  would 
seem  to  be  no  indication  for  them  that  is  not  as  well  met  by  opium  or 
morphine.  None  of  the  plants  containing  them  have  been  used  to  any  great 
extent,  although  Sanguinaria  Canadensis  was  formerly  occasionally  pre- 
scribed as  a  nauseating  expectorant  and  emetic.  The  "  Sanguinarine  "  of 
commerce  is  generally  a  mixture  of  the  alkaloids  with  other  constituents, 
and,  like  the  other  preparations  of  the  plant,  might  well  be  dispensed  with. 

U.  S.  P.  PREPARATIONS. 

Sanguinaria,  the  rhizome  of  Sanguinaria  Canadensis,  bloodroot,  collected 
in  autumn. 

Tinctura  /Sanguinarice,  1-2  c.c.  (15-30  mins.). 
Fluidextractum  Sanguinarice,  0.1-0.5  c.c.  (2-8  mins.). 

BIBLIOGRAPHY. 

H.  Meyer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix.,  p.  397. 
Schmidt.     Arch,  der  Pharmacie,  ccxxxix.,  p.  393. 

Anhalonium. — A  number  of  alkaloids,  some  resembling  morphine,  others 
strychnine  in  their  effects  on  animals,  have  recently  been  isolated  from  dif- 
ferent members  of  the  Anhalonium  genus  (Fam.  Cactacese).  In  Mexico,  and 
along  the  southern  boundary  of  the  United  States,  where  those  plants  are 
indigenous,  some  of  them  are  used  as  narcotics  in  the  religious  rites  of  the 
Indians  and  are  known  as  Pellote,  Peyotl,  or  Muscale  or  Mezcal  Buttons. 
The  symptoms  arise  for  the  most  part  from  the  cerebrum  and  differ  from  those 
of  opium  and  cannabis  indica  in  the  frequency  with  which  color  visions  are 
induced,  these  consisting  in  constantly  shifting  flashes  of  brilliant  colors. 
Mezcal  eating  is  not  followed  by  merriment  as  in  cannabis  nor  by  sleep  like 
morphine  but  depression  of  some  functions  is  indicated  by  the  imperfect  co- 
ordination of  the  movements,  the  retarded  perception  and  the  errors  in  the 
estimation  of  time.  The  exaltation  seems  to  be  caused  for  the  most  part  by 
one  of  the  alkaloids,  mezcaline.  Very  large  doses  have  induced  unpleasant 
symptoms  through  depression  of  the  respiration.  Anhalonium  and  pellotine, 
one  of  its  alkaloids,  have  been  used  as  narcotics  in  a  few  cases  of  insomnia. 

Lewin.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiv.,  p.  401 ;  xxxiv.,  p.  374. 
Heffter.     Ibid.,  xxxiv.,  p.  65  ;  xl.,  p.  385.    Mogilewa.  Ibid.,  xlix.,  p.  137. 
Prentiss  and  Morgan.     Med.  Kecord,  1896,  Aug.  22. 
Dixon,     Journ.  of  Physiol.,  xxv.,  p.  69. 


HYDRASTINE  AND  HYDRASTININE.  229 


iv.    TTVDRAsypra  AND  HYDRASTININE. 

Another  alkaloid  which  is  closely  related  to  those  of  opium  chem- 
ically and  pharmacologically,  is  Hydrastine,  which  occurs  in  the 
Hydrastis  Canadensis  (Golden  Seal)  along  with  Berberine  and  Cana- 
dine. 

Hydrastine  (C21H21NO6),  when  exposed  to  oxidizing  agents  such  as  potassium 
permanganate,  is  decomposed  into  opianic  acid  and  Hydrastinine  (CnH13NO3), 
another  alkaloid.  Narcotine  (C22H23NO7),  the  opium  alkaloid,  undergoes  a  simi- 
lar decomposition  into  opianic  acid  and  Cotarnine  (C12H15NO4).  Hydrastine  and 
narcotine  differ  only  in  a  hydrogen  atom  of  the  former  being  substituted  by 
—  OCH3  in  the  latter,  and  a  similar  relation  exists  between  hydrastinine  and 
cotarnine.  All  four  are  derivatives  of  isoquinoline.  The  action  of  hydrastis  is 
similar  to  that  of  hydrastine,  the  berberine  and  canadine  having  little  effect ;  the 
latter  is  as  poisonous  as  hydrastine,  but  is  present  only  in  very  small  quantities 
in  the  plant. 

Action.  —  Hydrastine  causes  in  frogs  an  increase  in  the  reflex  irrita- 
bility and  eventually  tetanus  exactly  resembling  that  produced,  by 
strychnine,  and  like  it  terminating  finally  in  paralysis.  Unlike  strych- 
nine, however,  it  weakens  and  eventually  paralyzes  the  muscles  in 
the  same  way  as  the  alkaloids  of  sanguinaria.  The  heart  is  rendered 
slow  and  weak,  partly  by  the  central  stimulation  of  the  inhibitory  ap- 
paratus and  partly  by  direct  action  on  the  muscle  fibres. 

In  mammals,  the  pulse  is  slowed  by  comparatively  small  quantities, 
while  somewhat  larger  doses  cause  general  feebleness,  tremor,  dyspnoea, 
and  incoordination  in  the  movements.  Very  large  quantities  elicit 
clonic  and  then  tonic  convulsions  and  tetanus,  during  which  the  respira- 
tion ceases.  The  pulse  is  slowed  at  first  from  stimulation  of  the  vagus 
centre,  is  afterwards  quickened  from  its  paralysis,  and  still  later  be^ 
comes  slow  again  from  direct  action  on  the  cardiac  muscle.  The 
blood-pressure  rises  from  constriction  of  the  arterioles  but  after- 
wards falls,  partly  from  their  dilatation  and  partly  from  the  weakness 
of  the  heart ;  the_constriction  of  the  arterioles  is  due  to  stimulation  of 
the  vaso-motor  centre  in  the  medulla.  Several  authors  have  asserted 
that"  the  injection  of  hydrastine  solution  is  followed  by  rhythmic  con- 
tractions of  the  uterus  similar  to  those  observed  during  labor,  but  this 
has  been  denied  by  others,  and  cannot  be  said  to  have  been  satisfac- 
torily established  either  by  experiment  or  by  clinical  experience. 
Another  statement  which  is  frequently  met,  is  that  hydrastis  and 
hydrastine  increase  the  secretion  of  the  bile,  but  this  is  founded  upon 
very  imperfect  experiments  and  is  in  all  probability  erroneous.  Hy- 
drastine has  no  local  anaesthetic  action. 

Hydrastine  then  stimulates  first  the  centres  of  the  medulla  oblongata, 
and  produces  slowing  of  the  pulse,  an  increased  arterial  tension  and 
accelerated  respiration.  Larger  quantities  stimulate  further  the  spinal 
cord  and  eventually  paralyze  both  medulla  and  cord.  In  addition 
to  this  central  action,  hydrastine  v/eakens  and  paralyzes  muscle,  this 


230  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

being  confined  to  the  hear t^  in  warm-blooded  animals,  but  extending 
to  the  ordinary  striated  muscle  of  the  frog. 

These  effects  would  appear  to  give  hydrastine  a  position  near  that  of 
thebaine,  though  it  differs  from  most  of  the  opium  alkaloids  in 
seeming  to  act  more  strongly  on  the  medulla  than  elsewhere  in  the 
central  nervous  system.  Its  action  on  the  heart  and  muscle  is  analo- 
gous to  that  of  several  of  the  opium  alkaloids.  Hydrastine  is  excreted 
as  such  in  the  urine,  and  does  not  form  hydrastinine  in  the  organism 
as  might  have  been  surmised  from  its  behavior  towards  oxidizing  sub- 
stances. When  it  is  administered  for  some  time,  a  cumulative  action 
is  said  to  be  developed. 

Canadine  in  small  quantities  produces  depression  and  drowsiness  followed 
by  complete  recovery  without  further  symptoms.  In  larger  quantities  v. 
Bunge  found  that  it  caused  a  short  stage  of  excitement,  which  was  followed 
by  depression  and  paralysis  of  the  central  nervous  system.  It  has  little  or 
no  effects  on  the  mammalian  circulation  when  administered  in  ordinary 
doses,  but  very  large  quantities  cause  weakness  and  arhythmia  of  the  heart. 
Its  injection  is  followed  by  violent  peristalsis  of  the  intestine  and  diarrhoea. 
Can&dine  is  present  in  only  very  small  quantity  in  the  Golden  Seal  and  has 
apparently  little  importance  in  therapeutics. 

Hydrastinine,  an  artificial  alkaloid  formed  from  hydrastine,  has  of 
late  years  attacted  a  certain  amount  of  attention  from  its  alleged  power 
of  arresting  hemorrhage.  It  seems  to  differ  from  hydrastine  in,caus- 
ing  no  marked  disturbance  of  the  centres  of  motion  and  feeling  save 
in  enormous  doses,  which  paralyze  the  nervous  system, "and,  in  the  frog, 
the  terminations  of  the  motor  nerves  in  muscle  (Santesson).  On  the 
other  hand,  its  action  on  the  medulla  oblongata  resembles  that  of  the 
parent  substance.  The  heart  is  slowed  somewhat  by  small  doses,  ap- 
parently from  stimulation  of  the  vagus  centre,  and  the  arterial  tension 
rises  further  than  after  hydrastine.  Unlike  the  latter,  however,  hy 

Idrastinine  causes  a  very  prolonged  augmentation  of  the  blood-pressure 
because  it  does  not  tend  to  depress  the  heart  to  the  same  extent  as  hy 
drastine.  In  fact,  several  authors  believe  that  it  increases  the  effi- 
ciency of  the  heart  movements  from  action  on  the  muscle,  although  the 
pulse  may  be  somewhat  slowed  by  stimulation  of  the  inhibitory  centre. 
After  very  large  quantities,  the  pulse  is  often  extremely  rapid  from 
paralysis  of  the  inhibitory  centre. 

The  cause  of  the  increased  arterial  tension  is  still  undecided.  There 
seems  to  be  undoubted  stimulation  of  the  vaso-motor  centre,  but  ac- 
cording to  some  writers,  the  peripheral  vessels  are  contracted  by  direct 
action  on  the  walls  as  well.  This  statement  seems  open  to  question, 
however,  none  of  the  'experiments  on  which  it  is  founded  being  alto- 
gether satisfactory ;  thus,  while  Falk  found  well  marked  contraction 
of  the  abdominal,  and  especially  of  the  renal  vessels,  v.  Bunge  denies 
that  the  renal  vessels  are  constricted.  It  has  been  repeatedly  stated 
that  hydrastinine  produces  rhythmical  contraction  of  the  uterus,  and 
even  abortion  in  animals,  but  this  does  not  seem  to  be  correct.  It  ap- 
pears to  have  no  direct  action  on  the  muscle  of  this  organ,  but  its  ves- 


HYDRASTINE  AND  HYDRASTININE.  231 

sels  undergo  constriction  like  those  of  the  rest  of  the  body,  and  this 
may  stop  haemorrhage  and  at  the  same  time  cause  asphyxia  of  the 
foetus  and  abortion.  It  must  be  stated,  however,  that  several  writers 
on  hydrastinine  hold  that  it  causes  contraction  of  the  uterus  through 
action  on  the  muscle,  and  the  question  deserves  further  investigation. 
Archangelsky  states  that  a  10  per  cent,  solution  of  hydrastinine  ap- 
plied locally  causes  dilatation  of  the  pupil,  which  reaches  its  maximum 
in  2-3  hours,  and  lasts  for  12-15  hours. 

PREPARATIONS. 

Hydrastis  (IT.  S.  P.),  Hydrastis  Rhizoma  (B.  P.),  the  rhizome  and  roots 
of  Hydrastis  Canadensis,  Golden  Seal. 

Fluldextractum  Hydrastis  (U.  S.  P.),  1-4  c.c.  (15-60  mins.). 

Extractum  Hydrastis  Liquidum  (B.  P.),  5-15  mins. 

Glyceritum  Hydrastis  (U.  S.  P.),  1-4  c.c.  (15-60  mins.). 

Tinctura  Hydrastis  (U.  S.  P.,  B.  P.),  1-4  c.c.  (15-60  mins.). 

Hydrastina  (U.  S.  P.),  white  bitter  crystals  almost  insoluble  in  water. 

Hydrastinince  Hydrochloridum  (U.  S.  P.),  0.03-0.1  G.  (£-2  grs.),  given  in 
solution  hypoderniically  or  by  the  mouth,  or  in  pills  or  tablets. 

Therapeutic  Uses.  —  Hydrastis  has  been  used  as  a  stomachic  bitter 
and  the  large  quantity  of  berberine  contained  in  it  would  seem  to  give 
it  a  place  along  with  the  simple  bitters.  It  has  also  been  credited  with 
some  obscure  action  on  the  mucous  membranes  when  locally  applied, 
through  which  it  is  said  to  benefit  many  forms  of  catarrhal  inflamma- 
tion. For  this  purpose  the  glycerite  may  be  used.  Besides  various 
conditions  in  which  its  use  was  attended  by  doubtful  success,  it  has 
been  used  in  haemorrhage  from  the  uterus ;  but  for  this  purpose, 
hydrastinine  ought  to  be  preferred,  as  it  causes  a  much  greater  con- 
striction of  the  peripheral  vessels  than  hydrastine,  and  acts  less  on 
the  heart.  The  conditions  in  which  it  is  indicated  seem  to  be  moder- 
ate haemorrhage,  for  which  no  contraction  of  the  uterine  walls  is  re- 
quired ;  for  example,  hydrastinine  is  of  value  in  excessive  menstrual 
flow,  while  in  post-partum  hemorrhage  it  seems  to  have  little  effect, 
because  here  the  haemorrhage  is  to  be  met  rather  by  inducing  contrac- 
tion of  the  uterine  walls  by  the  use  of  ergot  than  by  constricting  the 
vessels,  There  seems  no  reason  why  hydrastinine  should  not  be  used 
in  other  forms  of  haemorrhage,  for  it  does  not  act  more  on  the  uterine 
vessels  than  on  others  throughout  the  body. 

Hydrastinine  has  been  found  to  lessen  somewhat  the  irritability  of 
the  motor  areas  of  the  brain,  and  its  use  has,  therefore,  been  suggested 
in  epilepsy. 

Cotarnine  has  been  introduced  under  the  name  of  Stypticine  as  a  substitute 
for  hydrastinine  in  uterine  hemorrhage.  Dose,  0.02-0.03  G.  (|~4  gr.).  It 
resembles  hydrastinine  in  its  general  action  and  has  received  some  recom- 
mendation at  the  hands  of  gynecologists. 

BIBLIOGRAPHY. 

P.  Marfori.  Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii.,  p.  161.  Arch.  Ital.  de  Biol., 
xxviii.,  p.  191. 

K  Folk.     Virchow's  Arch.,  cxix.,  p.  399  ;  cxlii.,  p.  360. 


232  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Cerna.     Therap.  Gaz.,  1891,  pp.  289,  361. 

K.  v.  Bunge.     Arbeiten  a.  d.  pharmakolog.  Institut.  Dorpat,  xi.  and  xiL,  p.  119. 

Fellner.     Centralbl.  f.  Physiol.,  xi.,  p.  374. 

Santesson.     Skandin.  Arch.  f.  Physiologie,  vi.,  p.  308. 

Ronsse.     Arch,  de  Pharmacodynam. ,  iv.,  p.  207  ;  v.,  p.  21. 

Philipps  and  Pembrey.     Brit.  Med.  Jour.    1898,  ii.,  p.  1052. 

V.    OANNABIS   INDIOA. 

The  hemp  plant  possesses  no  pharmacological  interest  when  grown 
in  temperate  regions,  but  when  cultivated  in  warm  climates  as  in 
India,  Egypt  or  the  southern  United  States,  it  develops  products  which 
induce  marked  derangements  of  the  central  nervous  system.  The 
Indian  plant  was  formerly  supposed  to  be  a  distinct  species,  but  differs 
so  little  from  the  European  form  that  'botanists  now  consider  them 
merely  varieties.  The  old  name  of  Cannabis  Indica  has,  however, 
been  retained  in  medicine.  Its  introduction  into  Western  medicine 
dates  only  from  the  beginning  of  last  century,  but  it  has  been  used  as 
an  intoxicant  in  Asiatic  countries  and  in  Africa  since  unknown  time, 
and  under  the  names  of  Hashish,  Bhany,  Ganja,  Charas  or  Churrus, 
is  habitually  indulged  in  by  some  one  or  two  hundred  millions  of 
mankind.  Some  of  the  preparations  are  smoked  either  alone  or  mixed 
with  tobacco ;  others  form  an  intoxicating  drink,  while  in  others  it  is 
mixed  with  sugar  or  honey  and  taken  as  a  confection. 

The  active  principle  of  Indian  hemp  has  been  found  by  Wood,  Spivey  and 
Easterfield  to  be  a  red  oil  or  resin  boiling  at  a  high  temperature,  which  they 
term  Cannabinol ;  this  was  found  by  Marshall  to  induce  the  typical  effects  of 
cannabis  indica  in  man  and  animals.  Frankel  states  that  cannabinol  is  a  phe- 
nolaldehyde  of  the  formula  OH  •  C20H28COH. 

Symptoms.  —  The  effects  of  cannabis  indica  are  chiefly  due  to  the 
changes  in  the  central  nervous  system,  in  which  it  induces  a  mixture 
of  depression  and  stimulation  similar  to  that  seen  occasionally  under 
morphine.  Its  action  is  much  less  constant,  however,  and  seems  to 
depend  very  largely  on  the  disposition  and  intellectual  activity  of  the 
individual.  The  preparations  used  also  vary  considerably  in  strength, 
and  the  activity  of  even  the  crude  drug  seems  to  depend  very  largely 
on  the  climate  and  season  in  which  it  is  grown,  so  that  great  discrep- 
ancies occur,  in  the  accounts  of  its  effects.  Soon  after  its  administra- 
tion, the  patient  passes  into  a  dreamy,  semiconscious  state,  in  which  the 
judgment  seems  to  be  lost,  while  the  imagination  is  un trammeled  by 
its  usual  restraints.  The  dreams  assume  the  vividness  of  visions,  are 
of  boundless  extravagance,  and,  of  course,  vary  with  the  character  and 
pursuits  of  the  individual.  In  the  eastern  races  they  seem  generally 
to  partake  of  an  amorous  nature.  The  true  believer  sees  the  gardens 
of  paradise  and  finds  himself  surrounded  by  troops  of  houris  of  un- 
speakable beauty,  while  the  less  imaginative  European  finds  himself  un- 
accountably happy  and  feels  constrained  to  active  movement,  often  of  a 
purposeless  and  even  absurd  character.  Ideas  flash  through  the  mind 
without  apparent  continuity,  and  all  measurement  of  time  and  space 


CANNABIS  INDICA.  233 

is  lost.  True  hallucinations  may  appear,  but  are  often  absent,  the 
chief  features  of  the  action  being  merriment,  comfort,  well-being  and 
self-satisfaction.  Often  less  pleasant  thoughts  obtrude  themselves, 
however,  such  as  the  fear  of  impending  death  or  of  some  imminent  in- 
definite danger.  During  this  period,  the  consciousness  is  not  entirely 
lost,  for  the  patient  often  feels  that  his  dreams  are  unreal,  his  satisfaction 
unfounded  and  his  movements  ridiculous,  but  he  cannot  restrain  them  ; 
he  can  give  a  coherent  account  of  his  condition  when  aroused  and 
answer  questions  intelligently.  The  sensation  of  pain  is  lessened  or 
entirely  absent,  and  the  sense  of  touch  is  less  acute  than  normally. 
Later  the  dreams  alternate  with  periods  of  complete  unconsciousness, 
from  which  the  patient  can  be  aroused  easily,  and  the  symptoms 
eventually  pass  into  tranquil  sleep,  from  which  he  awakes  refreshed, 
and,  as  a  rule,  without  any  feeling  of  depression  or  nausea.  In  the 
majority  of  cases  the  preliminary  stage  of  exaltation  is  very  short  or 
entirely  absent  in  Europeans,  the  first  effects  of  the  drug  often  being 
heaviness,  drowsiness,  noises  in  the  ears  and  numbness  of  the  extrem- 
ities, which  pass  into  deep  sleep.  According  to  Dixon  the  drug  is 
much  more  exhilarating  when  inhaled  than  when  swallowed,  and  this 
may  account  for  some  of  the  variations  in  its  action.  In  some  cases, 
acute  mania  and  convulsive  attacks  have  been  developed,  and  among 
the  natives  of  India  catalepsy  occasionally  occurs. 

In  animals,  the  effects  of  cannabis  indica  seem  to  resemble  those  in 
man  and  present  the  same  marked  variations  ;  a  stage  of  exaltation  with 
increased  movement  is  sometimes  present  and  is  followed  by  depres- 
sion, lassitude  and  sleep.  The  reflex  excitability  is  first  increased  and 
then  diminished  in  frogs.  Vomiting  is  often  induced  in  dogs  and  cats, 
but  cannabis  indica  differs  from  opium  in  producing  no  disturbance  of 
the  digestion  and  no  constipation.  The  heart  is  generally  accelerated 
in  man,  when  the  drug  is  inhaled  ;  the  intravenous  injection  in  animals 
slows  the  pulse  partly  through  inhibitory  stimulation  and  partly 
through  direct  action  on  the  heart  muscle.  This  action  on  the  heart  is 
stated  by  Dixon  to  be  the  cause  of  death  after  poisonous  quantities,  for 
he  found  the  respiration  persist  for  some  seconds  after  standstill  of  the 
heart.  The  pupil  is  generally  somewhat  dilated.  Polyuria  is  stated 
to  occur  in  dogs  in  which  cannabinol  appears  to  be  excreted  by  the 
kidneys  in  combination  with  glycuronic  acid  (Frankel). 

Death  from  acute  poisoning  is  extremely  rare,  and  recovery  has  oc- 
curred after  enormous  doses.  The  continued  abuse  of  hashish  in  the 
East  sometimes  leads  to  mania  and  dementia,  but  does  not  cause  the 
same  disturbance  of  nutrition  as  opium,  and  the  habitual  use  of  small 
quantities,  which  is  almost  universal  in  some  Eastern  peoples,  does  not 
seem  .detrimental  to  them,  although  among  Europeans  it  might  possibly 
be  as  fatal  as  that  of  morphine.  Some  tolerance  is  rapidly  acquired. 


234  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


PKEPAKATIONS. 

Gannabis  Indica  (U.  S.  P.,  B.  P. ),  Indian  hemp,  the  flowering  tops  of  the 
female  plant  of  Cannabis  sativa  (hemp),  grown  in  the  East  Indies. 

Extractum  Cannabis  Indices  (U.  S.  P.,  B.  P.),  0.02-0.06  G.  (i-1  gr.). 

Fluidextractum  Cannabis  Indicce  (U.  S.  P.),  0.1-0.3  c.c.  (2-5  mins.). 

TINCTURA  CANNABIS  INDICLE  (U.  S.  P.,  B.  P.),  1-2  c.c.  (15-30  mins.). 

The  preparations  vary  extremely  in  strength  and  many  are  entirely  inert, 
especially  when  they  have  been  kept  some  time.  The  unofficial  prepara- 
tions, such  as  u  cannabin  tannate, "  cannabinon,  etc.,  seem  to  be  no  more 
reliable  than  the  pharmacopceial  ones,  and  offer  no  advantages  at  all  com- 
mensurate with  their  price. 

Therapeutic  Uses.  —  Cannabis  indica  is  used  as  a  hypnotic  in  cases  of 
sleeplessness  from  nervous  exhaustion  and,  less  often,  from  pain.  It  is 
not  nearly  so  reliable  as  opium,  and  in  fact  produces  sleep  in  only  about 
50  per  cent,  of  the  cases,  according  to  some  authors.  On  the  other  hand, 
it  does  not  disturb  the  digestion  and  produces  no  subsequent  nausea 
and  depression,  and  may  therefore  be  employed  in  some  cases  in  which 
opium  is  contraindicated.  It  is  of  use  in  some  cases  of  migraine,  and 
has  been  prescribed  as  a  substitute  for  opium  in  mental  diseases. 

Lactucarium  (U.  S.  P.),  the  dried  juice  of  Lactuca  virosa,  the  common 
lettuce,  is  reputed  to  have  some  hypnotic  properties.  It  contains  neutral 
bitter  substances,  lactucin  and  lactucon,  and  it  has  been  stated  recently  that 
traces  of  hyoscyamine  and  atropine  are  also  present.  In  any  case  its  action 
is  so  feeble  that  half  an  ounce  has  been  administered  to  a  dog  without  effect, 
and  it  seems  quite  unnecessary  to  include  it  in  the  pharmacopoeia. 

U.  S.  P. — Tinctura  Lactucarii. 

Syrupus  Lactucarii. 

BIBLIOGRAPHY  OF  CANNABIS  INDICA. 

Hare.     Therapeutic  Gazette,  1887,  p.  225. 
Wood.     Proc.  Amer.  Phil.  Soc.,  1869,  p.  226. 

Zuco  u.  Vignolo.  Arch.  Ital.de  Biol.,  xxiii.,  p.  409.  Bericht.  der  Berl.  Chem.  Ge- 
sellsch.,  1895,  iv.,  p.  558. 

Marshall.     Lancet,  1897,  i.,  p.  235.     American  Medical  Journal,  1898,  ii.,  p.  882. 

Dixoji.     Brit.  Med.  Journ.,  1899,  ii.,  p.  136. 

Frankel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlix.,  p.  266. 

VI.    APOMORPHINE. 

When  morphine  is  acted  on  by  acids  and  by  some  other  dehydrat- 
ing agents,  it  loses  a  molecule  of  water,  and  a  new  alkaloid  is  formed, 
Apomorphine  (C17H17NO2). 

Through  this  change  the  action  of  the  original  alkaloid  is  consider- 
ably modified  ;  apomorphine  preserves  the  stimulant,  but  loses  to  a 
great  degree  the  depressant  action  of  morphine  on  the  central  nervous 
system.  This  stimulant  action  extends  over  the  whole  central  nervous 
system  in  animals,  but  is  most  developed  in  the  "  vomiting  centre  "  of 
the  medulla  oblongata. 

Symptoms.  —  In  man,  apomorphine  in  doses  of  5-10  mg.  (^-J  gr.) 


APOMOEPHINE. 


235 


induces  within  10-15  minutes  nausea  and  vomiting,  accompanied  by 
the  usual  attendant  phenomena,  but  with  no  symptoms  which  cannot 
be  directly  included  in  these.  Very  often  the  nausea  passes  off  imme- 
diately after  the  evacuation  of  the  stomach,  but  when  larger  quantities 
have  been  administered,  repeated  vomiting  and  retching  may  occur. 
Occasionally  depression  and  sleep  follow  the 
emesis  after  even  small  doses.  FlG-  19- 

The  attendant  symptoms  are  profuse  saliva- 
tion, increased  secretion  of  the  mucous  glands 
of  the  nose,  throat  and  bronchial  passages, 
tears  and  a  cold  perspiration.  A  feeling  of 
depression  and  muscular  weakness  and  accel- 
eration of  the  pulse  are  also  well-known 
symptoms  accompanying  nausea  and  vomit- 
ing, and  are  present  after  apomorphine. 
These  are  all  to  be  regarded  as  sequelae  of  the 
emetic  action,  however,  and  not  as  due  to 
the  direct  action  of  the  drug  on  the  glands 
and  other  organs.  In  a  few  instances  the 
depression  and  weakness  have  passed  into 
alarming  collapse,  but  no  actual  fatality  is 
recorded  from  the  use  of  apomorphine. 

Very  small  doses  of  apomorphine  may 
induce  the  secondary  symptoms  without  actual 
vomiting.  Thus  the  saliva,  perspiration, 
tears  and  other  secretions  may  be  augmented 
by  quantities  which  are  too  small  to  act  as 
emetics,  though  there  is  no  question  that 
these  are  due  to  the  commencing  emetic 

action  apomorphine.      The  volume   in- 

.   .  ,.    .  spired  in  each  2%  mins.  is  meas- 

111     dogS     and     Cats,     Small  quantities  ellClt  ured  along  the  perpendicular,  the 

. ,  w     ,  •  iii  i  time  aloug  the  horizontal    line. 

the  same  effects  as  in  man,  but  larger  doses    At  first  about  GOO  c.c.  represents 


600-  : 


are  followed  by  symptoms  of  general  nervous 
stimulation.  In  the  herbivora,  which  are 
incapable  of  vomiting,  these  symptoms  follow 
the  injection  of  comparatively  small  quantities  and  are  much  more 
marked.  The  rabbit,  for  example,  becomes  restless  and  easily  alarmed  ; 
it  moves  about,  climbs  up  the  walls  of  its  cage  and  gnaws  anything  it 
can  reach.  Circus  movements  are  developed  very  often,  especially  in 
the  dog,  the  animal  running  unceasingly  in  a  circle  and  striking  against 
obstacles  in  its  path,  apparently  unconscious  of  all  its  surroundings 
and  overcome  by  the  impulse  to  continual  movement.  The  respiration 
is  very  much  accelerated  (Fig.  19).  After  very  large  quantities  the 
movements  become  less  coordinated,  and  eventually  tetanic  convul- 
sions set  in,  during  which  the  respiration  ceases,  while  the  heart  con- 
tinues to  beat  for  some  time  afterward. 

Apomorphine  induces  vomiting  through  changes  in  the  medulla  ob- 


236  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

longata  and  not  by  irritation  of  the  stomach.  This  is  shown  by  the 
fact  that  it  acts  much  more  quickly  and  in  smaller  doses,  when  it  is 
injected  hypodermically  than  when  it  is  swallowed,  and  also  by  the  fact 
that  if  the  medulla  be  brushed  with  apomorphine  solution,  vomiting 
follows  immediately.  .  It  is  even  disputed  whether  apomorphine  has 
any  effect  on  the  gastric  movements  at  all,  for  Batelli  states  that  the 
stomach  remains  quite  passive  during  vomiting,  while  Schiitz  found  it 
undergoing  antiperistaltic  movements  towards  the  cardiac  orifice.  In 
any  case  the  movements  of  the  stomach  play  an  unimportant  part  in 
the  evacuation  of  its  contents  by  apomorphine,  and  all  the  phenomena 
in  man  are  to  be  ascribed  to  medullary  action. 

Apomorphine  is  said  to  have  some  anaesthetic  effects  on  the  cornea 
when  a  solution  is  dropped  upon  it.  It  causes  cloudiness  and  conse- 
quent dimness  of  sight,  however,  and  has  not  been  used  practically 
for  this  purpose.  Apomorphine  is  not  excreted  into  the  stomach 
like  morphine,  nor  has  it  been  found  in  the  mucous  membranes  of 
the  air  passages,  and  it  is  possible  that  it  is  decomposed  in  the 
tissues. 

The  symptoms  induced  by  apomorphine  resemble  in  some  degree 
those  following  morphine  in  many  animals,  for  here  too  the  first  symp- 
tom is  vomiting  accompanied  by  signs  of  excitement,  which  are,  how- 
ever, generally  attended  by  those  of  depression  of  some  parts  of  the 
central  nervous  system.  The  similarity  between  the  effects  of  apomor- 
phine and  of  morphine  on  the  cat,  for  example,  is  particularly  striking. 
In  man,  however,  the  effects  are  very  different,  for  apomorphine  seems 
to  have  lost  all  the  depressant  action  of  the  parent  body,  although  here 
again  it  must  be  remembered  that  morphine  occasionally  causes  vomit- 
ing, so  that  apomorphine  does  not  depart  so  far  from  the  type  of  the 
opium  alkaloids  as  would  at  first  sight  appear. 

In  the  frog,  apomorphine  causes  a  transient  stimulation  of  the  central  nervous 
system,  followed  by  depression  and  paralysis.  Larger  quantities  weaken  and 
paralyze  the  muscles  and  the  heart  through  direct  action  on  the  fibres.  The 
muscular  action  may  also  be  demonstrated  on  excised  muscles,  in  which  the 
elasticity  is  lessened,  and  the  contractions  become  weaker  and  eventually  cease 
entirely.  This  weakening  in  the  contraction  of  the  muscles  has  not  been 
observed  in  mammals,  and  is  quite  distinct  from  the  feeling  of  weakness  accom- 
panying nausea  in  man,  for  the  latter  is  certainly  of  cerebral  origin.  No  emesis 
is  induced  in  frogs,  although  these  animals  are  not,  like  the  herbivora,  incapable 
of  vomiting. 

Apocodeine  is  formed  from  codeine  in  the  same  way  as  apomorphine  from 
morphine,  but  it  differs  entirely  from  apomorphine  in  its  action  and  resembles 
nicotine  in  paralyzing  the  sympathetic  ganglia.  It  causes  purgation  when 
injected  hypodermically,  apparently  from  removing  the  normal  inhibition  of  the 
bowel  movements  (Dixon).  If  codeine  be  heated  with  hydrochloric  acid  (B.  P.), 
apomorphine  is  formed,  and  not  apocodeine. 

PREPARATIONS. 

APOMOKPHINJE  HYDROCHLORIDUM  (U.  S.  P.,  B.  P.),  3-6  mg.  (^VrV  gr.). 
INJECTIO  APOMOEPHIN^E  HYPODERMICA  (B.  P.),  1  per  cent.,  5-10  mins. 


APOMORPHINE.  237 

Apomorphine  hydrochlorate  is  a  grayish-white  crystalline  substance,  very 
soluble  in  water  and  turning  dark  green  or  even  black,  especially  when  kept 
long  in  solution.  This  change  in  color  does  not  appear  to  impair  its  activity 
appreciably.  The  doses  given  above  are  those  for  hypodermic  use  to  induce 
vomiting.  The  same  quantity  may  be  given  by  the  mouth  as  an  expectorant. 

Therapeutic  Uses.  —  Apomorphine  is  used  chiefly  as  an  emetic,  and 
for  some  purposes  presents  several  advantages  over  the  older  drugs 
employed  with  this  object,  inasmuch  as  it  acts  more  promptly  and  can 
be  administered  by  the  hypodermic  needle,  while  the  other  emetics 
have  to  be  given  by  the  mouth,  which  is  a  serious  drawback  in  cases 
of  poisoning.  The  more  important  of  these  older  drugs  are  ipecacu- 
anha, tartar  emetic  (antimony),  ammonium  carbonate,  the  sulphates  of 
copper  and  zinc  and  alum. 

Vomiting  is  not  now  such  an  important  method  of  treatment  as  it 
was  formerly,  and  the  emetics  are  less  frequently  employed  to  evacuate 
the  stomach  than  other  less  heroic  measures  such  as  the  passage  of  the 
stomach  tube.  Emesis  may  be  indicated  in  poisoning,  and  here  apo- 
morphine  is  especially  useful.  But  in  the  great  majority  of  cases  a 
better  method  of  treatment  is  repeated  washing  of  the  stomach  by 
means  of  the  stomach  tube,  for  in  narcotic  poisoning  apomorphine  not 
infrequently  fails  to  act  owing  to  the  depression  of  the  vomiting  centre, 
and  in  corrosive  poisoning  a  certain  amount  of  danger  attends  its  use, 
as  the  pressure  on  the  walls  of  the  stomach  exerted  by  the  contraction 
of  the  diaphragm  and  abdominal  muscles  may  lead  to  the  rupture  of 
the  weakened  walls  of  the  organ.  In  irritant  poisoning,  on  the  other 
hand,  the  reflex  vomiting  set  up  is  generally  sufficient  to  empty  the 
stomach,  and  the  indications  are  rather  to  allay  the  gastric  irritation 
than  to  increase  it  by  causing  violent  movements  of  the  abdominal 
walls  by  apomorphine.  Emetics,  such  as  apomorphine,  have  been  used 
occasionally  to  cause  pressure  on  other  abdominal  organs,  e.  <?.,  on  the 
gall-bladder  in  order  to  dislodge  a  calculus  or  plug  of  mucus  in  the 
ductus  choledochus,  but  this  treatment  is  not  to  be  advised,  owing  to 
the  risk  of  rupture  of  the  gall-bladder.  Occasionally  emetics  are  used, 
especially  in  children,  to  expel  bodies  from  the  air  passages,  as  violent 
movements  of  expiration  are  produced  during  emesis.  Apomorphine 
is  comparatively  rarely  used  for  this  purpose,  however.  In  cases  of 
choking  due  to  foreign  bodies  lying  in  the  pharynx,  vomiting  is  often 
beneficial,  but  the  emetics  act  too  slowly  to  be  of  benefit  here. 

Occasionally  vomiting  is  still  induced  as  a  preliminary  to  treatment 
of  various  conditions  not  related  to  the  alimentary  canal ;  thus  before 
commencing  the  treatment  of  malaria  with  quinine,  the  stomach  is 
sometimes  emptied  by  an  emetic,  while  the  bowel  is  evacuated  by  a  purge. 

A  second  use  of  emetics  is  in  inflammatory  conditions  of  the  res- 
piratory  passages ;  the  object  here  is  to  induce  an  increased  secretion 
without  producing  emesis,  and  very  small  quantities  are  therefore 
used.  The  special  condition  in  which  this  class  of  remedies  is  of  ser- 
vice is  bronchial  irritation  with  a  sticky  mucous  secretion  which  causes 


238  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

cough,  but  can  only  be  expectorated  with  difficulty.  The  indications 
are  for  a  mild  and  prolonged  action  such  as  can  be  induced  by  small 
doses  of  ipecacuanha,  antimony  and  similar  bodies,  rather  than  for  the 
more  transient  effects  of  apomorphine,  but  the  latter  has  been  advised 
by  some  authorities.1 

Emesis  is  contraindicated  in  all  conditions  in  which  a  sudden  rise  of 
blood-pressure  may  be  dangerous,  as  in  atheroma,  fatty  heart  or  aneu- 
rism, and  where  there  is  any  danger  of  rupture  of  the  abdominal  walls 
or  organs  as  in  hernia,  advanced  pregnancy  (especially  if  there  be  any 
tendency  to  abortion)  gastric  ulcer,  and  generally  in  impacted  gall- 
stone. 

BIBLIOGRAPHY. 

Siebert.     Inaug.  Diss.,  Dorpat,  1871.     Wagner's  Archiv.  f.  Heilkunde,  xii.,  p.  522. 
QuehL     Inaug.  Diss.,  Halle,  1872. 

Harnack.  Arch,  f.  exp.  Path.  u.  Pharm.,  ii. ,  p.  254;  iii.,  p.  64.  Therapeut. 
Monatsh.,  1892,  p.  270. 

Thumas.     Virchow's  Archiv,  cxxiii.,  p.  44. 

Guinard.     Schmidt's  Jahrb.,  ccxli.,  p.  130. 

Dixon.     Jour,  of  Phys.,  xxx.,  p.  97.     (Apocodeine.) 


VII.     PRUSSIC   ACID. 

Prussic  or  hydrocyanic  acid  differs  entirely  from  the  other  acids  in 
its  pharmacological  action,  and  has  therefore  to  be  described  apart 
from  them. 

The  pure  acid  is  scarcely  ever  seen  save  in  the  chemical  laboratory, 
and  is  an  extremely  dangerous  body  to  handle,  as  it  is  very  volatile 
and  its  fumes  when  inhaled  may  produce  death  within  a  few  seconds. 
It  is  generally  met  with  in  a  very  dilute  solution,  which  is  formed  by 
the  decomposition  of  one  of  its  salts. 

In  nature,  prussic  acid  occurs  in  the  secretion  of  some  of  the  myria- 
poda,  and  in  the  decomposition  products  of  a  few  glucosides,  of  which 
Amygdalin  is  the  best  known.  Amygdalin  is  in  itself  practically  in- 
active, but  may  be  decomposed  by  dilute  acids  or  by  a  ferment,  emul- 
sin,  which  is  generally  found  associated  with  it  in  plants.  The  prod- 
ucts of  its  decomposition  are  prussic  acid,  benzaldehyde  and  glucose 
(see  p.  68). 

Both  amygdalin  and  emulsin  occur  in  the  bitter  almond  and  in  the 
kernels  of  a  number  of  fruits,  such  as  the  apple,  cherry,  prune,  plum 
and  apricot.  In  smaller  quantities  they  have  been  found  in  the  bark 
and  leaves  of  several  of  these  trees  and  in  the  laurel  (Prunus  lauro- 
cerasusj.  In  the  sweet  almond  emulsin  occurs,  but  no  amygdalin. 
When  bitter  almonds  are  rubbed  into  a  paste  with  water,  prussic  acid 
is  formed  by  the  action  of  the  ferment  on  amygdalin,  and  very  large 
quantities  of  such  a  paste  may  give  rise  to  unpleasant  symptoms, 
especially  in  children.  A  more  dangerous  substance  is  the  oil  of  bitter 

1  Apomorphine  is  occasionally  mentioned  as  a  hypnotic,  but  the  preliminary  vomit- 
ing would  certainly  prevent  its  use  for  this  purpose  unless  in  quite  exceptional  condi- 
tions. 


PJIUSSIC  ACID.  239 

almonds,  which  consists  of  benzaldehyde  and  prussic  acid  in  a  loose 
combination  and  in  very  varying  proportions.  Several  liqueurs  are 
distilled  from  kernels  and  fruits  containing  amygdalin,  and  therefore 
possess  a  variable  percentage  of  prussic  acid.  The  best  known  of  these 
are  Kirschwasser  and  Maraschino.  Laurel  water  and  the  preparations 
of  Virginian  cherry  bark  contain  benzaldehyde  and  prussic  acid, 
although  these  are  in  too  small  quantity  to  have  any  poisonous  action. 
Prussic  acid  and  its  salts  have  practically  the  same  action,  although 
none  of  the  latter  are  so  poisonous  as  the  free  acidt  Cyanogen,  (CN)2, 
also  resembles  prussic  acid  in  its  effects,  but  is  not  so  active. 

The  ferrocyanides  and  other  double  cyanides  are  in  most  cases  harmless 
but  other  compounds,  from  which  prussic  acid  is  formed  in  the  organism, 
are  poisonous.  The  organic  combinations  containing  the  —  CN  radicle 
form  two  series,  the  Nitriles  t  in  which  the  nitrogen  is  trivalent  (e.  </., 
CH3  —  C  =  N),  and  the  Isonitriles,  or  Carbylamines,  in  which  the  alkyl  is  at- 
tached to  the  nitrogen  (e.  g. ,  CH3  —  N  ^  C).  These  compounds  are  all  much 
less  poisonous  than  prussic  acid,  and  the  nitriles  are  said  to  differ  from  it  in 
their  effects,  inasmuch  as  the  chief  symptoms  caused  by  them  arise  from 
gastro-intestinal  irritation.  The  isonitriles  are  more  poisonous  than  the 
nitriles  and  resemble  the  acid  more  closely  in  their  action.  Both  nitriles 
and  isonitriles  give  rise  to  the  formation  of  prussic  acid  in  the  tissues. 

Symptoms  and  Action.  —  Prussic  acid  first  stimulates  and  then  para- 
lyzes the  central  nervous  system  in  mammals,  but  it  acts  on  so  many 
forms  of  living  matter  that  it  merits  the  designation  of  a  general  proto- 
plasm poison.  The  fatal  dose  in  man  is  believed  to  be  about  0.05-0.08 
G.  (1-1 J  gr.)  of  the  pure  acid,  certainly  a  much  larger  quantity  than  is 
fatal  in  cases  of  poisoning  with  some  of  the  alkaloids  and  glucosides. 
Prussic  acid  acts  much  more  rapidly  than  these,  however,  and  has  thus 
gained  its  reputation  of  being  the  most  dangerous  of  poisons. 

After  very  large  doses  in  mammals,  there  may  be  practically  no 
symptoms ;  the  animal  falls  to  the  ground  with  a  slight  convulsive 
movement  or  a  scream,  and  death  follows  in  a  few  seconds  from  simul- 
taneous arrest  of  the  heart  and  respiration. 

In  smaller  quantities,  prussic  acid  has  a  bitter,  acrid,  burning  taste, 
which  is  accompanied  by  salivation,  and  is  followed  by  numbness  in  the 
mouth  and  throat.  A  sensation  of  warmth  in  the  stomach  is  followed 
by  nausea  and  vomiting,  confusion  and  headache,  dyspnoea,  slow  pulse, 
and  general  muscular  weakness.  The  pupils  are  widely  dilated  and 
the  eyeballs  protrude,  as  generally  occurs  in  asphyxia.  Unconscious- 
ness follows,  and  then  violent  convulsions,  which  pass  into  paralysis 
with  involuntary  evacuation  of  the  contents  of  the  bladder  and  bowel, 
the  respiration  becomes  extremely  slow  and  eventually  ceases,  while 
the  heart  continues  to  beat  for  some  time  afterwards. 

In  frogs,  no  convulsions  occur,  the  symptoms  pointing  to  a  paralysis 
of  the  central  nervous  system  without  preliminary  stimulation,  except 
in  that  the  respiration  is  somewhat  quick  and  dyspnceic. 

In  mammals,  the  Central  Nervous  System  is  first  stimulated  and  then 


240 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


paralyzed,  but  the  action  seems  to  be  developed  more  fully  in  the 
medulla  oblongata  and  lower  parts  of  the  brain  than  in  the  cerebral 
cortex,  for  the  convulsions  resemble  those  produced  by  stimulation  of 
the  hind-brain,  although  the  subsequent  paralysis  seems  to  include  all 
parts  of  the  central  axis. 

The  peripheral  Nerves  and  the  Muscles  are  weakened  and  eventually 
paralyzed   when  suspended  in  an  atmosphere  of  the  gas,  but  unless 


FIG. 


c 


Tracing  of  the  movements  of  the  diaphragm  (respiration)  of  the  rabbit  under  a  large  but  not  fatal 
dose  of  cyanide  of  potash  injected  intravenously.  A-B,  normal  respiration.  At  B  1  mg.  injected  ;  the 
respiratory  movements  are  much  larger.  At  C  recovery.  Note  the  short  duration  of  the  stimulation. 

very  large  quantities  are  injected,  they  are  not  much  affected  in  the 
living  animal.  When  prussic  acid  in  solution  is  applied  locally  to  the 
Skin,  it  produces  a  numbness  and  partial  loss  of  sensation,  but  this 
does  not  follow  in  general  poisoning.  The  anaesthetic  action  is  well 
seen  on  brushing  the  leg  of  a  frog  with  a  weak  solution,  for  no  reflex 
can  be  elicited  from  subsequent  irritation  of  the  limb,  although  it  is 
moved  on  irritation  of  other  parts  of  the  body,  which  shows  that  the 
motor  nerves  and  the  spinal  cord  are  still  intact. 

The  Respiration  is  rendered  quicker  and  deeper  by  the  injection  or 
inhalation  of  small  quantities  of  prussic  acid.  During  the  convulsions 
it  is,  of  course,  irregular,  and  afterwards  generally  becomes  extremely 
slow  and  deep  and  then  ceases.  After  very  large  quantities  it  may 
cease  within  a  few  seconds.  These  changes  are  produced  by  primary 
stimulation  and  subsequent  paralysis  of  the  medullary  centre. 

The  Circulation  is  altered  mainly  through  the  action  on  the  central 
nervous  system,  although  prussic  acid  also  acts  directly  on  the  heart. 
The  stimulation  of  the  inhibitory  centre  generally  slows  the  pulse, 
but  this  is  accompanied  by  a  very  considerable  rise  in  blood-pressure 
from  increased  activity  of  the  vaso-constrictor  centres.  This  central 


PRUSSIC  ACID.  241 

stimulation  later  passes  into  paralysis  and  the  blood-pressure  falls,  from 
the  depression  of  the  vaso-motor  centres,  but  the  heart  does  not  gen- 
erally regain  its  normal  rhythm,  because  although  the  inhibitory  stimu- 
lation has  passed  off,  the  cardiac  muscle  is  now  directly  affected,  and 
its  movements  therefore  remain  somewhat  slow.  During  the  con- 
vulsions the  arterial  pressure  rises  again,  but  afterwards  the  progres- 
sive weakening  of  the  heart  leads  to  a  slow  and  imperfect  circulation. 
In  the  frog's  heart,  prussic  acid  causes  slowing  and  standstill  long  be- 
fore the  peripheral  nerves  and  muscles  are  affected. 

If  very  large  quantities  be  injected  intravenously,  or  inhaled,  the 
heart  may  cease  contracting  for  a  few  seconds,  and  then  recommence  a 
slow  and  feeble  beat,  which  is  very  soon  arrested  again.  This  is  prob- 
ably due  to  primary, action  on  the  inhibitory  centre,  followed  by  direct 
paralysis  of  the  heart. 

Batelli  has  shown  that  prussic  acid  injected  hypodermically  lessens 
the  movements  of  the  stomach.  The  temperature  remains  constant  or 
rises  somewhat  after  small  doses,  but  falls  rapidly  when  toxic  symptoms 
appear. 

Nutrition.  —  Besides  its  specific  action  on  the  central  nervous  system, 
prussic  acid  exercises  a  depressant  action  on  protoplasm  in  general,  and 
may  therefore  be  called  a  general  protoplasm  poison,  although  some 
of  the  bacteria  are  but  little  affected  by  it.  Both  plants  and  animals 
are  retarded  in  their  movements  and  in  their  nutritive  processes  by  its 
presence,  although  they  may  recover  and  show  no  subsequent  deteriora- 
tion provided  the  poison  acts  only  during  a  short  time  and  in  suffi- 
cient dilution.  For  example,  the  development  of  seeds  is  hindered 
by  the  presence  of  prussic  acid,  but  proceeds  when  it  is  withdrawn  ; 
yeast  cells  cease  their  activity,  and  the  insectivorous  plant  Drosera 
no  longer  moves  its  tentacles  in  the  presence  of  cyanides  or  prussic  acid 
(Darwin).  This  action  in  plants  is  probably  due  to  the  poison  arrest- 
ing the  activity  of  the  ferments,  for  it  has  proved  to  have  a  deleterious 
action  on  many  of  the  known  ferments. 

The  effects  of  prussic  acid  on  the  mammalian  tissues  have  been  ex- 
amined by  G-sppert  in  a  long  and  careful  research.  He  found  that  the 
oxygen  absorbed  by  the  tissues  was  much  lessened  by  prussic  acid, 
whereas  i*.  was  to  be  expected  that  a  convulsive  poison,  such  as  that 
under  discussion,  would  cause  an  increased  waste  in  the  tissues  and  a 
corresponding  rise  in  the  oxygen  used ;  yet  during  the  most  powerful 
convulsions  after  prussic  acid,  the  absorption  of  oxygen  is  often  dis- 
tinctly lower  than  in  the  normal  resting  animal.  After  some  time  the 
consumption  of  oxygen  again  increases,  although  it  does  not  regain  the 
normal  standard  unless  complete  recovery  occurs ;  the  carbonic  acid 
actually  formed  by  the  tissues  falls,  owing  to  the  lessened  oxidation, 
and  Geppert  proceeded  to  prove  that  the  imperfect  oxidation  is  due  to 
the  fact  that  the  tissues  are  unable  to  absorb  the  oxygen  brought  to 
them  by  the  blood  cells ;  that,  in  fact,  a  change  occurs  in  the  proto- 
plasm, which  retards  the  normal  respiration  of  the  cell.  In  conse- 

16 


242  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

quence  of  this,  the  oxyhaemoglobin  of  the  blood  is  not  reduced  in  the 
capillaries,  so  that  the  venous  blood  has  the  same  bright-red  color  as 
the  arterial.  Prussic  acid  seems  to  be  rapidly  changed  to  other  prod- 
ucts in  the  tissues,  however,  provided  a  lethal  dose  has  not  been  given, 
and  as  this  process  goes  on  the  protoplasm  recovers  its  oxygen- 
absorbing  power,  the  expired  air  becomes  less  rich  in  oxygen  and 
richer  in  carbonic  acid,  and  the  venous  blood  assumes  its  ordinary 
dark  color.  Lactic  acid  and  sugar  are  found  in  the  blood  in 
unusually  large  quantities  during  the  action  of  prussic  acid ;  these 
are  invariably  present  when  the  oxidation  of  the  tissues  is  imperfect 
from  any  cause. 

The  changes  in  the  central  nervous  system  are  produced  by  smaller 
quantities  and  somewhat  more  rapidly  than  those  in  the  metabolism, 
and  they  also  last  longer.  The  dilatation  of  the  blood  vessels  from 
the  depression  of  the  vaso-constrictor  centre  may  probably  cooperate 
with  the  lessened  absorption  of  oxygen  to  produce  the  bright  red  color 
of  the  venous  blood,  for  it  stands  to  reason  that  a  more  rapid  circula- 
tion through  the  capillaries  must  lessen  the  amount  of  oxygen  given  up 
by  the  blood. 

The  diminution  in  the  oxygen  absorption  by  the  tissues  is  of  interest 
in  relation  to  the  retardation  of  the  ferment  action  in  plants,  for  Jacquet 
has  shown  that  the  tissues  oxidize  mainly  by  a  ferment  action,  and 
there  thus  seems  to  be  an  entire  correspondence  between  the  changes 
produced  in  the  metabolism  of  plants  and  animals  by  prussic 
acid. 

Prussic  acid  is  changed  to  sulphocyanides  in  the  tissues,  and  is 
partly  excreted  in  the  urine  in  this  form,  while  part  of  it  undergoes 
further  and  unknown  changes.  This  combination  of  prussic  acid  and 
sulphur  bodies,  such  as  the  proteids,  seems  to  arise  by  simple  chemical 
processes,  without  the  intervention  of  living  protoplasm  being  neces- 
sary. 

In  the  living  body  prussic  acid  does  not  form  any  combination  with 
the  haemoglobin  of  the  red  blood  cells,  but  in  the  drawn  blood  it 
appears  to  form  cyanha3moglobin,  a  loose  combination  which  differs 
slightly  from  haemoglobin  in  its  spectrum  and  is  reduced  with  greater 
difficulty,  so  that  the  blood  retains  its  red  color  longer.  If  normal 
blood  be  brought  in  contact  with  a  solution  of  peroxide  of  hydrogen, 
it  effervesces  owing  to  the  liberation  of  oxygen,  but  the  oxyhsemoglobin 
remains  unchanged ;  if,  however,  prussic  acid  be  present  no  effer- 
vescence occurs,  but  the  haemoglobin  is  at  once  changed  to  methaemo- 
globin.  In  cases  of  poisoning  with  cyanides,  the  dependent  parts  of 
the  body  often  present  a  bright  red  color  instead  of  the  usual  post- 
mortem lividity,  and  this  seems  due  to  the  cyanhaemoglobin  retaining 
its  red  color,  while  ordinary  oxyhaemoglobin  is  reduced. 


PEUSSIC  ACID.  243 

PREPARATIONS. 

Acidum  Hydrocyanicum  Dilutum  (U.  S.  P.,  B.  P.),  a  two  per  cent,  solu- 
tion formed  from  potassium  ferrocyanide  or  silver  cyanide.  It  is  a  colorless 
fluid  with  a  characteristic  smell  and  taste,  and  ought  not  to  be  kept  long, 
as  it  is  liable  to  decomposition  ;  much  of  that  actually  used  in  medicine  is 
partially  decomposed  and  therefore  under  two  per  cent,  in  strength.  Dose, 
0.1-0.5  c.c.  (2-8  mins.). 

Argenti  Cyanidum  (U.  S.  P.),  is  used  in  medicine  only  for  the  formation  of 
the  dilute  hydrocyanic  acid. 

A  number  of  other  preparations  contain  prussic  acid,  generally  in  very 
variable  quantity.  Thus  in  the  U.  S.  P.  the  preparations  of  bitter  almonds, 
except  the  expressed  oil,  contain  it,  and  the  volatile  oil  is,  in  fact,  dangerous 
owing  to  the  large  proportion  of  prussic  acid  sometimes  present.  Another 
series  of  preparations  containing  it,  though  only  in  minute  quantities,  is 
that  of  the  bark  of  the  wild  cherry,  Prunus  Virginiana.  In  the  British 
Pharmacopoeia  the  bitter  almond,  Virginian  cherry  and  the  cherry -laurel 
water  contain  it,  but  only  in  harmless  quantities.  It  is  also  present  in  the 
tincture  of  chloroform  and  morphine,  B.  P. 

Therapeutic  Uses. — The  uses  of  prussic  acid  at  the  present  day  are 
very  few.  Externally  it  is  applied  to  itching  surfaces  to  cause  numb- 
ing and  insensibility  of  the  sensory  nerve  terminations,  but  care  must 
be  taken  that  the  surface  is  unbroken,  or  unpleasant  and  even  danger- 
ous symptoms  may  be  induced.  It  is  also  used  internally  in  vomiting, 
especially  in  that  occurring  in  pregnancy,  and  seems  to  be  beneficial 
occasionally.  It  was  formerly  used  extensively  as  a  sedative  in  cough, 
but  was  generally  prescribed  along  with  opium  or  other  narcotics,  and 
it  seems  unlikely  that  the  hydrocyanic  acid  had  any  effect. 

In  Poisoning  with  prussic  acid  or  the  cyanides,  the  treatment  is  that 
of  poisoning  in  general  —  thorough  evacuation  of  the  stomach,  warmth 
and  general  measures  against  collapse.  A  number  of  so-called  anti- 
dotes have  been  proposed,  such  as  atropine,  which  there  is  no  reason 
to  suppose  would  be  of  benefit,  for  it  has  been  found  useless  in  animal 
experiments.  The  intravenous  injection  of  sodium  sulphide  and  hypo- 
sulphite has  been  advised  on  the  theory  that  the  comparatively  harm- 
less sulphocyanide  would  be  formed,  and  animals  seem  to  be  able 
to  survive  an  otherwise  lethal  dose  when  this  is  done.  Peroxide  of 
hydrogen  has  also  been  suggested,  in  order  to  form  innocuous  oxidation 
products  with  the  prussic  acid.  Artificial  respiration  should  be 
resorted  to  when  necessary,  as  the  cyanide  is  comparatively  quickly 
rendered  inactive,  and  the  recovery  is  rapid  when  it  once  sets  in.  But 
in  many  cases  life  is  extinct  before  medical  aid  can  be  called. 

BIBLIOGRAPHY. 

Kolliker.     Virchow's  Archiv,  x.,  p.  272. 

Preyer.     Die  Blausaure,  Bonn,  1868. 

Hoppe-Seyler.     Medicinisch-chemisch.  Untersuch.,  1866-1870,  p.  133. 

Gaethgens.     Ibid.,  p.  324. 

Zillessen.   Ztsch.  f.  phys.  Chem.,  xv.,  p.  398. 

Boehm  u.  Knie.     Arch.  f.  exp.  Path.  u.  Pharm.,  ii.,  p.  129. 


244  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Geppert.     Ztschr.  f.  klin.  Med.,  xv.,  pp.  208  and  307. 

Robert.  Ueber  Cyanmethsemoglobin  und  den  Nachweis  der  Blausaure.  Stuttgart, 
1891.  Lehrb.  d.  Intoxicationen,  2nd  ed.,  pp.  94-99. 

Sch'dr.     Naegeli-Kollikersche  Festschrift,  Zurich,  1891. 

Lang.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv.,  p.  247. 

Pascheles.     Ibid.,  p.  281. 

JBunge.     Ibid.,  xii.,  p.  41.      (Cyanogen.) 

Heymanns  et  Masoin.     Arch,  de  Pharmacodynamique,  iii.,  p.  359.      (Nitriles.) 

Hunt.     Arch,  intemat.  de  Pharmacodyn.  et  de  Therap.,  xii.,  p.  <*.47, 

Haldane.     Journ.  of  Phys.,  xxv.,  p.  230. 

VIII.     CAFFEINE. 

In  a  num  ,er  of  plants  used  in  different  parts  of  the  world  to  form 
beverages  and  condiments,  there  are  found  the  xanthine  compounds, 
Caffeine,  Theobromine  and  Theophylline  (Theocine),  which  have  been 
employed  in  therapeutics  of  late  years,  and  have,  therefore,  acquired 
a  double  importance  as  drugs  and  as  articles  of  diet.  The  wide- 
spread use  of  preparations  of  these  by  uncivilized  peoples  is  a  curious 
and  unexplained  fact,  especially  as  they  possess  neither  peculiar  taste 
nor  odor  to  guide  in  the  selection  of  the  plants  in  which  they  exist. 
Besides,  caffeine  and  its  allies  in  moderate  quantities  induce  no  marked 
symptoms,  such  as  follow  the  use  of  alcohol,  opium  or  hashish  and 
explain  their  use  among  widely  separated  peoples.  On  the  contrary, 
the  only  effects  to  be  observed  are  a  brightening  of  the  intellectual 
faculties  and  an  increased  capacity  for  mental  and  physical  work. 
Coffee,  the  use  of  which  is  derived  from  the  Arabians,  is  the  berry  of 
Coffea  Arabica  and  contains  caffeine  ;  tea,  the  leaves  of  Thea  Chinensis, 
contains  caffeine  along  with  theophylline.1  Cacao,  cocoa  or  chocolate 
is  derived  from  the  seeds  of  Theobroma  cacao,  a  tree  indigenous  in 
Brazil  and  Central  America,  and  contains  theobromine.  In  central 
Africa,  the  Cola  or  Kola  nut  (Sterculia  acuminata)  is  used  by  the  na- 
tives, and  contains  caffeine  with  small  quantities  of  theobromiue.2 
In  Brazil,  Guarana  paste  is  formed  from  the  seeds  of  Paullinia  sor- 
bilis,  and  contains  caffeine  and  theobromine,  while  in  the  Argentine 
Republic,  Yerba  Mate  or  Paraguay  tea  (Ilex  Paraguay ensis)  is  'used 
to  form  a  beverage  which  contains  a  very  small  quantity  of  caf- 
feine. Another  species  of  Ilex  is  met  with  in  Virginia  and  Caro- 
lina under  the  name  of  Apalache  tea  or  Youpon,  and  also  contains 
caffeine. 

These  three  principles,  caffeine,  theobromine  and  theophylline,  are 
purine  derivatives  closely  related  to  the  xanthine  bodies  found  in  the 
urine  and  tissues  of  the  animals.  The  members  most  closely  approach- 
ing the  vegetable  forms  are  xanthine,  paraxanthine  and  heteroxan thine  ; 
the  last  is  a  monomethylxanthine,  while  paraxanthine  is  a  dimethyl- 
xanthine  isomeric  with  theobromine  and  theophylline,  and  caffeine  is 

1  Tea  was  formerly  supposed  to  contain  theine,  but  this  has  proved  to  be  identical 
with  caffeine. 

a  Kolanine,  or  colanine,  which  was  at  one  time  supposed  to  be  a  new  body,  seems  to 
be  a  compound  of  tannic  acid  with  these  xanthine  derivatives. 


CAFFEINE.  245 

trimethylxanthine.     The  structural  formulae  may  serve  to  indicate  more 
clearly  the  close  relationship  of  these  bodies. 

Xanthine.  Theobromine. 

NH— C— N    \  CH3N— C— N       \ 

of    1_NH>H  5    J-NCH  >H 

HN— CO  NH— CO 

Theophylline.  Caffeine. 

v  CHSN-C-N       \ 

>CH         oi  |-NCH  >CH 

CH3N— CO 


Action.  —  These  all  resemble  each  other  in  most  points  of  their 
pharmacological  action,  although  caffeine  acts  on  the  central  nervous 
system  as  well  as  on  the  kidneys,  muscle  and  heart,  while  theobromine 
has  comparatively  little  effect  except  on  the  last  three. 

Central  Nervous  System. — In  mammals  the  injection  of  large  quan- 
tities of  caffeine  is  followed  by  symptoms  closely  resembling  those  in- 
duced by  strychnine.  The  reflex  irritability  is  remarkably  increased, 
the  lightest  touch  being  followed  by  powerful  contraction  of  almost  all 
the  muscles  of  the  body.  After  a  time  these  contractions  occur  with- 
out any  apparent  stimulus,  and  culminate  in  tonic  convulsions  which 
last  for  several  seconds.  During  these  the  respiration  ceases  from  the 
respiratory  muscles  being  involved  in  the  spasm  and  occasionally  it 
fails  to  be  reinstated  when  the  convulsions  pass  off.  In  other  instances 
the  spasms  become  weaker  and  occur  at  longer  intervals  ;  the  respira- 
tion diminishes  in  frequency  and  depth  and  eventually  ceases. 

In  man,  smaller  quantities  of  caffeine  stimulate  the  central  nervous 
system,  in  particular  that  part  associated  with  the  psychical  functions. 
The  ideas  become  clearer,  thought  flows  more  easily  and  rapidly,  and 
fatigue  and  drowsiness  disappear.  Not  infrequently,  however,  con- 
nected thought  is  rendered  more  difficult,  for  impressions  follow  each 
other  so  rapidly  that  the  attention  is  distracted,  and  it  requires  more 
and  more  effort  to  limit  it  to  a  single  object.  If  the  quantity  ingested 
is  small,  however,  the  results  are  of  distinct  benefit  in  intellectual  work. 
The  capacity  for  physical  exertion  is  also  augmented,  as  has  been  dem- 
onstrated repeatedly  by  soldiers  on  the  march,  and  more  recently  by 
more  exact  experiments  with  the  ergograph.  The  stimulation  of  the 
higher  nervous  centres  is  often  evidenced  by  the  insomnia  and  restless- 
ness which  in  many  people  follow  indulgence  in  coffee  or  tea  late  at 
night.  Kraepelin  has  investigated  the  effects  of  caffeine  from  the  psy- 
chological point  of  view,  and.  finds  that  both  tea  and  coffee  facilitate 
the  reception  of  sensory  impressions  and  also  the  association  of  ideas, 
especially  in  fatigue,  while  the  transformation  of  intellectual  concep- 
tions into  actual  movements  is  retarded.  This  he  regards  as  due  to 
stimulation  of  the  highest  or  controlling  functions  of  the  brain,  caffeine 


246  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

acting  on  the  same  parts  as  are  first  affected  by  alcohol  and  the  methane 
derivatives,  but  altering  them  in  the  opposite  direction.  The  effects 
of  caffeine  on  the  acuteness  of  the  senses  has  been  demonstrated  by  the 
greater  accuracy  of  touch  under  its  influence. 

Large  quantities  of  caffeine  often  cause  headache  and  some  confu- 
sion, and  in  rare  cases  of  special  susceptibility  a  mild  form  of  delirium 
may  be  elicited,  or  noises  in  the  ears  and  flashes  of  light  may  indicate 
derangement  of  the  special  senses.  The  pulse  is  quickened,  and  oc- 
casionally palpitation  and  uneasiness  in  the  region  of  the  heart  are 
complained  of.  Convulsive  movements  of  the  muscles  of  the  hand 
and  tremor  in  different  parts  of  the  body  have  also  been  recorded  in 
some  cases.  These  effects  are  induced  only  with  difficulty  in  habitual 
drinkers  of  tea  or  coffee,  so  that  the  continued  administration  of  small 
quantities  of  caffeine  evidently  gives  rise  to  tolerance. 

The  symptoms  induced  by  caffeine  in  the  lower  mammals  are  due 
for  the  most  part  to  its  acting  on  the  spinal  cord  in  the  same  way  as 
strychnine,  though  small  doses  may  act  on  the  brain,  for  they  often 
elicit  restlessness  and  timidity  without  any  marked  change  in  the  reflex 
excitability.  The  centres  in  the  medulla  oblongata  are  also  involved 
in  the  effects,  as  is  indicated  by  a  rise  in  the  blood-pressure  from  stim- 
ulation of  the  vaso-motor  centre,  acceleration  of  the  breathing,  and  oc- 
casionally some  slowness  of  the  pulse  from  action  on  the  respiratory 
and  pneumogastric  centres.  The  intracranial  bloodvessels  are  said  to 
be  dilated. 

Frogs  show  no  nervous  symptoms  that  cannot  be  ascribed  to  action 
on  the  spinal  cord,  and  in  some  species  these  are  elicited  with  con- 
siderable difficulty  owing  to  the  muscular  action  described  below. 

On  comparing  the  effects  of  caffeine  and  strychnine  on  the  central 
nervous  system  it  will  be  found  that  while  there  is  a  general  similarity 
in  their  action,  the  latter  causes  more  marked  stimulation  of  the  lower 
divisions  and  has  less  action  on  the  cerebrum  in  mammals  and  man. 
They  both  produce  a  general  increase  in  the  activity  of  nerve  cells, 
but  caffeine  acts  more  on  the  psychical,  strychnine  more  on  the  vital 
and  reflex  functions. 

Theophylline  resembles  caffeine  in  its  action  on  the  central  nervous 
system,  while  theobromine  induces  few  or  no  symptoms  of  stimula- 
tion. The  monomethyl-xanthines  and  xanthine  itself  stimulate  the 
central  nervous  system  in  the  frog  (Schmiedeberg). 

The  Muscular  action  of  caffeine  is  best  seen  in  the  Rana  temporaria 
(grass  frog),  although  it  is  also  induced  in  other  species  of  frogs,  and 
some  rigidity  may  be  elicited  in  mammals  by  very  large  doses.  When 
a  few  drops  of  caffeine  are  injected  into  the  leg  of  a  frog  there  follows 
a  peculiar  stiffness  and  hardness  in  the  muscles  around  the  point  of  in- 
jection, which  slowly  spreads  to  other  parts  of  the  body  and  induces 
the  appearance  of  rigor  mortis.  The  same  effect  is  observed  when 
teased  muscle  fibres  are  subjected  to  a  caffeine  solution  under  a  high- 
power  microscope.  The  fibres  contract,  become  white  and  opaque,  and 


CAFFEINE.  247 

look  stiff  and  inflexible  ;  the  transverse  striae  disappear,  while  the  lon- 
gitudinal become  more  easily  visible  (Fig.  21).  This  appearance  is 
due  to  the  death  and  rigor 

mortis  of  the  fibres.     Fiirth  FIG.  21. 

states    that   the    myogen    of 
muscle  is  formed  into  myo- 
genfibrin   and  coagulated  by        I 
the  addition  of  caffeine  to  its       ( 
solutions  outside  the  body,  so       m 
that   the    rigor    induced    by 
caffeine  seems  due  to  a  com-      Bjjj 
paratively     simple     reaction      ii 
between  the  poison   and  the 
proteids  of  the  muscle  fibre. 


In  Small  quantities  Caffeine  A  muscular  fibre  of  the  frog  (highly  magnified).  A, 
intfaacAa  ±V,«  iwi+okili'tir  ^f  normal  5  B> after  the  application  of  caffeine  solution.  The 
increases  the  irritability  OI  coarse  stri*  in  B  are  the  folds  of  the  sarcolemma. 

muscle  as  well  as  its  absolute 

strength  and  extensibility,  that  is,  the  muscle  contracts  on  a  weaker 
stimulus  and  against  a  greater  load  than  it  does  normally.  The 
amount  of  work  done  before  fatigue  sets  in  is  also  increased,  unless 
when  large  quantities  are  applied,  when  the  capacity  for  work  is  less- 
ened ;  and  with  the  first  appearance  of  rigor  it  ceases  to  react  to 
stimuli  altogether.  Sobieranski  has  recently  shown  that  in  ordinary 
doses  caffeine  increases  the  work  done  by  the  human  muscles  when 
they  are  stimulated  by  electric  shocks.  The  universally  recognized 
effect  of  tea  and  coffee  in  increasing  the  capability  for  physical  work 
and  in  relieving  fatigue  has  generally  been  regarded  as  due  to  changes 
in  the  nerve  cells,  but  according  to  Kraepelin  and  others  is  really  of 
peripheral  origin  and  explained  by  the  direct  action  on  the  muscle. 
While  the  action  of  theobromine  on  the  central  nervous  system  is 
much  less  marked  than  that  of  caffeine,  muscle  enters  into  rigor  after 
the  former  more  readily  and  xanthine  exceeds  even  theobromine  in  its 
power  to  produce  this  change. 

The  action  of  caffeine  on  the  Circulation  is  exerted  in  two  directions, 
on  the  vaso-motor  centre  in  the  medulla  and  on  the  heart  itself.  Along 
with  the  rest  of  the  central  nervous  system,  the  vaso-motor  area  un- 
dergoes stimulation  and  the  smaller  arteries  are  therefore  contracted, 
causing  a  marked  rise  in  the  arterial  pressure. 

In  the  frog's  heart  caffeine  in  very  small  quantities  is  found  to  in- 
crease the  absolute  strength,  that  is,  the  heart  contracts  against  a 
greater  aortic  pressure  than  it  would  normally,  and  at  the  same  time 
the  amount  of  blood  expelled  by  each  beat  is  slightly  increased.  The 
rhythm  is  generally  somewhat  accelerated  by  small  doses,  but  this  ef- 
fect is  often  of  very  short  duration.  On  the  absorption  of  larger 
quantities,  the  heart  first  becomes  slower  and  its  volume  smaller, 
then  the  apex  ceases  to  relax  with  the  rest  of  the  ventricle  and 
remains  white  and  contracted,  and  eventually  the  whole  heart  passes 


248  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

into  a  condition  of  rigor  exactly  resembling  that  seen  in  the  skeletal 
muscles. 

When  moderate  quantities  of  caffeine  are  injected  intravenously  in 
mammals,  the  heart  is  accelerated,  without  any  marked  change  in  the 
extent  of  systole  or  diastole.  The  increased  rate  is  independent  of  any 
action  ou  the  regulatory  mechanism  of  the  heart,  for  it  is  seen  in  hearts 
in  which  the  accelerans  has  been  cut  and  the  inhibitory  apparatus 
paralyzed  by  atropine.  It  is  probably  due  to  direct  action  on  the 
heart  muscle  for,  as  has  been  stated,  an  analogous  increase  in  irrita- 

FIG.  22. 


Tracing  of  the  ventricle  of  the  dog's  heart :  A,  normal ;  B,  after  caffeine.  The  lever  moves  upwards 
during  systole,  downwards  during  diastole.  The  only  alteration  caused  by  caffeine  is  acceleration. 
The  slightly  larger  excursion  in  diastole  in  B  is  mechanical.  (Contrast  tracings  under  digitalis.) 

bility  occurs  in  voluntary  muscle.  The  increased  irritability  of  the 
cardiac  fibres  also  accounts  for  the  fact  that  stimulation  of  the  vagus 
is  followed  by  less  slowing  of  the  heart  after  caffeine  than  before  its 
administration.  In  man  the  heart  rhythm  is  often  found  slower  after 
caffeine,  and  this  appears  to  be  due  to  stimulation  of  the  inhibitory 
centre  in  the  medulla  oblongata,  the  increased  inhibition  proving  more 
than  sufficient  to  counterbalance  the  acceleration  which  would  arise  from 
the  direct  action  of  the  caffeine  on  the  heart  muscle.  After  large 
quantities  of  caffeine  the  heart  becomes  weak  and  irregular  and  after 
death  it  is  found  in  diastole.  The  increased  rate  of  the  heart  beat  is 
not  always  accompanied  by  an  increase  in  the  amount  of  blood  expelled 
in  a  unit  of  time  (Bock),  although  this  is  often  the  case.  Apparently 
the  contractions  of  the  ventricle  follow  each  other  so  rapidly  that  the 
time  is  often  insufficient  for  the  inflow  of  the  usual  amount  of  blood. 
The  increase  in  the  blood-pressure  under  caffeine  is  therefore  tojbe 
ascribed  for  the  most  part  to  the  action  on  the  vaso-motor  centre,,  al- 
though not  infrequently  this  is  supplemented  by  an  increased  efficiency 
of  the  heart.  Theobromine  and  xanthine  possessing  but  little  action  in 


CAFFEINE.  249 

the  vaso-motor  centre,  scarcely  raise  the  blood-pressure  although  they 
have  the  same  effect  on  the  heart  as  caffeine.  Theobromine  causes 
some  dilatation  of  the  coronary  arteries  when  it  is  perfused  through 
.,  the  heart,  while  caffeine  is  devoid  of  this  action. 

The  Respiration  is  quickened  and  strengthened  by  caffeine,  owing  to 
a  stimulant  action  on  the  medullary  centre.  This  effect  on  the  respira- 
tion is  seen  in  the  improvement  of  the  respiration  in  cases  of  dangerous 
poisoning  with  alcohol,  opium  and  other  drugs  which  prove  fatal  by 
failure  of  the  respiration,  but  is  much  less  marked  in  normal  animals. 

The  Temperature  has  been  found  to  be  raised  by  caffeine  through  its 
action  on  the  nervous  centres  and  perhaps  on  the  muscles.  The  in- 
crease is,  however,  comparatively  insignificant  (0.5-1°  C.)  and  is  seen 
only  in  cases  in  which  an  almost  poisonous  dose  has  been  used. 

The  Alimentary  Tract  is  not  affected  by  caffeine,  but  after  theobro- 
mine  discomfort  and  loss  of  appetite  are  sometimes  complained  of, 
probably  owing  to  changes  in  the  gastric  mucous  membrane.  These 
are  much  more  marked  after  even  small  doses  of  theophylline,  and  small 
haemorrhages  and  erosions  have  been  found  in  the  stomach,  both  in  man 
and  animals  (Allard). 

Kidney. — The  most  important  property  of  caffeine  from  a  thera- 
peutic point  of  view  is  its  power  of  increasing  the  secretion  of  urine. 
It  is  an  everyday  experience  that  strong  coffee  or  tea  increases  the 
urine  to  a  much  greater  extent  than  the  same  amount  of  water,  and 
this  has  been  shown  to  be  due  to  the  caffeine  contained  in  these  bev- 
erages. It  is  still  disputed  how  caffeine  causes  diuresis,  for  while  the 
most  generally  accepted  view  is  that  of  Schroeder,  that  caffeine  acts 
directly  on  the  renal  cells,  some  investigators  hold  that  the  increased 
urinary  secretion  is  due  to  local  changes  in  the  renal  circulation.  As  a 
general  rule  the  vessels  are  dilated  and  the  kidney  volume  is  enlarged 
during  caffeine  diuresis,  but  this  may  be  merely  an  accompaniment 
and  not  the  cause  of  the  increased  activity.  In  any  case  the  diuresis 
is  due  to  changes  within  the  organ  and  is  quite  independent  of  the 
action  of  the  drug  in  other  parts  of  the  body.  These  may  in  fact 
counteract  the  real  action  and  prevent  the  diuresis,  through  stimula- 
tion of  the  vaso-constrictor  centre,  which  retards  the  circulation  in  the 
kidney  and  lessens  the  amount  of  fluid  reaching  the  renal  cells  (Schroe- 
der). This  inhibitory  action  of  the  vaso-motor  centre  may  be  elimi- 
nated by  such  medullary  depressants  as  chloral,  under  which  the  caf- 
feine diuresis  may  be  elicited  with  much  greater  certainty.  Theobro- 
mine has  a  more  constant  effect  on  the  kidney  and  causes  even  greater 
activity  in  that  organ  than  caffeine,  and  this  was  explained  by 
Schroeder  as  being  due  to  its  having  little  or  no  stimulant  effect  on 
the  vaso-constrictor  centre.  Theophylline  appears  to  increase  the 
urine  more  than  any  other  of  (the  group,  with  the  possible  exception  of 
paraxanthine. 

In  the  caffeine  diuresis,  the  fluid  part  of  the  urine  is  increased 
chiefly,  but  the  solids  also  undergo  an  augmentation,  though  not  to 
the  same  extent.  Among  the  solids  the  chief  increase  is  seen  in  the 


250 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


FIG.  23. 


sodium  chloride,  the  nitrogenous  constituents  undergoing  less  alteration 
although  they  also  rise  in  amount ;  a  small  amount  of  sugar  is  often  found 

in  the  urine,  more  especially  if  the  food 
has  contained  large  quantities  of  sugar- 
forming  substances,  but  this  glycosuria 
is  probably  due  merely  to  the  large  quan- 
tities of  fluid  sweeping  some  of  the  sugar 
of  the  blood  along  with  it,  and  does 
not  indicate  any  dangerous  alteration  in 
the  renal  epithelium  or  in  the  metab- 
olism. 

The  excretion  of  large  quantities  of 
fluid  in  the  urine  is,  of  course,  accom- 
panied by  a  diminution  of  the  fluids  of 
the  blood,  but  the  latter  soon  recuperates 
itself  from  the  tissues.  If  there  is  any 
accumulation  of  liquid,  such  as  oedema,  it 
is  drained  into  the  blood  to  replace  the 
fluid  thrown  out  by  the  kidney,  and  caf- 
feine may  accordingly  be  used  to  remove 
cedema  or  dropsy  iu  this  way.  If  no  such 
accumulation  exists,  the  blood  draws  on 
the  fluids  of  the  intestine  and  stomach, 
and  their  withdrawal  leads  to  the  sensa- 
tion of  thirst.  As  a  diuretic,  caffeine  is 
distinctly  inferior  to  theobromine  ;  in  the 
first  place  because  the  diuresis  is  less 
certain  and  is  often  accompanied  by  ner- 
vous symptoms — sleeplessness  and  rest- 
lessness ;  and  secondly  because  the  in- 
crease in  the  secretion  is  smaller  and 
lasts  for  a  shorter  time. 

Excretion. — Caffeine  is  excreted  in  the 
urine  to  a  very  small  extent  as  such. 
During  its  passage  through  the  body  it 
loses  its  methyl  groups  and  first  becomes 
dimethyl-  and  then  monomethylxanthine. 
Eventually  xanthine  is  formed  and  this 
probably  breaks  up  into  urea.  In  the 
urine  are  found  small  quantities  of  the 
unchanged  drug,  accompanied  by  larger 
quantities  of  dimethylxanthine  and  mono- 
methylxanthine. After  theobromine  and 
theophylline  some  of  the  unchanged  drug 
is  found  in  the  urine  along  with  monomethylxanthine. 

The  exact  order  in  which  the  methyl  groups  are  lost  in  the  tissues  ap- 
pears to  differ  in  different  animals ;  in  the  dog  all  three  isomeric  di- 
methylxanthines  are  formed  from  caffeine  and  after  large  doses  appear  in 


Caffeine  diuresis  in  a  rabbit.  The 
amount  of  urine  passed  in  ten  minutes 
is  represented  by  the  height  of  the  rec- 
tangles. The  first  of  these,  A-B,  repre- 
sent the  normal  secretion.  At  B  a  small 
dose,  and  at  C  a  large  dose  of  caffeine 
was  injected  intravenously,  and  the 
secretion  is  accordingly  increased.  The 
shaded  part  of  the  rectangles  represents 
the  amount  of  solids  in  the  urine.  It 
will  be  noted  that  these  are  increased  but 
not  to  the  same  extent  as  the  fluid.  The 
dotted  line  represents  the  average 
height  of  the  blood-pressure  during  each 
period  often  minutes.  The  animal  had 
received  a  large  dose  of  chloral  to  de- 
press the  vaso-motor  centre  and  the 
heart,  and  caffeine  had,  therefore,  little 
or  no  effect  on  the  height  of  the  blood- 
pressure. 


CAFFEINE.  251 

the  urine,  although  theophylline  predominates,  while  in  the  rabbit  and  in 
man  paraxanthine  is  formed  in  larger  amounts.  The  monomethylxanthines 
are  also  excreted  in  different  proportions  in  different  animals,  heteroxanthine 
prevailing  in  man  and  the  rabbit. 

PREPARATIONS. 

CAFPEINA  (U.  S.  P.,  B.  P.),  long,  white,  silky  crystals,  without  odor,  but 
possessing  a  bitter  taste,  but  little  soluble  in  cold  water,  more  so  in  alcohol, 
still  more  so  in  boiling  water.  0.05-0.3  G.  (1-5  grs.). 

CAFFEINA  CITRATA  (U.  S.  P.),  CAFFEINE  CITRAS  (B.  P.),  a  white  powder, 
consisting  of  a  weak  chemical  combination  of  citric  acid  and  caffeine.  It  is 
decomposed  by  mixture  with  more  than  3  parts  of  water.  0.1-0.5  G. 
(2-8  grs.). 

CAFFEINA  CITRATA  EFFERVESCENS  (U.  S.  P.),  CAFFEINE  CITRAS  EFFER- 
VESCENS  (B.  P.),  a  mixture  of  citrated  caffeine  with  sodium  bicarbonate,  tar- 
taric  acid  and  sugar.  On  throwing  the  powder  in  water  it  effervesces, 
owing  to  the  acids  acting  on  the  bicarbonate  and  liberating  carbonic  acid. 
This  preparation  is  an  extremely  weak  one,  containing  only  1  per  cent,  of 
caffeine  in  the  U.  S.  P.  and  about  2  per  cent,  in  the  B.  P. 

Caffeine  is  best  prescribed  either  in  powder  or  in  tablets  formed  from 
either  of  the  first  two  preparations.  It  may  also  be  given  in  water  with 
salicylate  of  soda,  which  aids  its  solution. 

THEOBROMINA  (unofficial)  is  a  crystalline  powder  even  less  soluble  than 
caffeine,  and  is  absorbed  with  difficulty  when  given  alone.  It  is  generally 
prescribed  in  doses  of  0.5  G.  (8  grs.)  three  times  a  day,  but  larger  quantities 
may  be  given.  Solutions  of  salicylate  of  soda  dissolve  it  much  more  readily 
than  pure  water. 

DITJRETINE  and  Agurine  are  double  salts  of  sodium-theobromine  with  the 
salicylate  and  acetate  of  sodium  respectively  and  are  much  more  soluble  than 
theobromine.  The  dose  is  0. 5-1  G.  three  times  a  day,  either  in  powder  form  or 
in  solution. 

Theocine,  an  artificial  theophylline,  is  a  white  crystalline  powder,  slightly  sol- 
uble in  water.  Dose,  0.2-0.3  G.  (3-5  grs.)  in  powder  or  tablets. 

Guarana  (U.  S.  P.),  a  brown  paste  derived  from  the  seeds  of  Paullinia  sor- 
bilis  and  containing  caffeine  and  theobromine  along  with  some  tannic  acid. 

Fluidextractum  Guarance  (U.  S.  P.),  3-8  c.c. 

Numerous  preparations  of  Kola  nut  are  now  put  on  the  market,  but  the 
pure  principles  are  preferable. 

Therapeutic  Uses.  —  The  action  of  caffeine  on  the  central  nervous 
system  has  led  to  its  employment  in  a  number  of  different  conditions. 
Thus,  in  nervous  exhaustion  it  may  be  used  to  stimulate  the  brain,  and 
in  collapse  its  action  on  the  vaso-motor  and  respiratory  centres  has  been 
found  of  value  —  the  blood-pressure  rises,  the  whole  tone  of  the  circu- 
lation is  improved  and  the  respiration  becomes  quicker  and  less  shallow. 
In  narcotic  poisoning  with  failing  respiration,  caffeine  may  be  used  to 
stimulate  the  centre  in  place  of  strychnine  or  atropine;  in  opium 
poisoning  more  particularly,  strong  coffee  has  long  been  used,  but 
caffeine  might  be  substituted  with  advantage.  Its  stimulant  action  on 
the  brain,  and  more  especially  on  the  respiration,  renders  it  an  antidote 
in  dangerous  cases  of  alcoholic  poisoning  also.  Some  forms  of  migraine 
and  headache  are  relieved  by  caffeine,  but  in  others  it  seems  rather  to 
intensify  the  pain  ;  this  action  has  been  attributed  to  its  dilating  the 
cerebral  vessels.  Kola  preparations  are  often  advised  as  general  tonics 
in  weakness  and  neurasthenia. 


252  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Caffeine  has  been  used  largely  for  its  action  on  the  heart  and  is  often 
said  to  be  a  substitute  for  digitalis,  though  as  a  matter  of  fact,  it  can- 
not replace  the  latter,  the  action  of  the  two  on  the  heart  being  entirely 
dissimilar.  In  cases  of  heart  weakness  without  marked  dilatation  and 
incompetency  of  the  valves,  it  may  be  of  service  as  it  increases  the 
activity  of  the  ventricle,  but  its  reputation  in  cases  of  cardiac  disease 
is  due  mainly  to  the  removal  of  dropsy  through  its  diuretic  action. 
The  contraction  of  the  arterioles  following  the  use  of  caffeine  may  also 
be  of  service  in  feeble  action  of  the  heart. 

In  their  action  on  the  kidney  the  members  of  the  caffeine  series 
stand  preeminent,  no  other  drug  producing  such  a  copious  flow  of  urine 
as  either  caffeine  or  theobromine.  As  has  been  explained  already,  the 
latter  is  to  be  preferred  to  caffeine  as  a  diuretic,  and  may  be  used  in 
all  cases  in  which  there  is  a  pathological  accumulation  of  fluid  in  the 
body,  whether  of  cardiac,  hepatic  or  renal  origin.  The  results  are 
most  brilliant,  however,  in  cases  of  cardiac  dropsy,  and  here  it  may 
be  prescribed  along  with  one  of  the  digitalis  series.  It  must  be  em- 
phasized, however,  that  in  these  cases  it  cannot  supplant  digitalis,  but 
merely  aids  in  the  removal  of  the  fluid  which  is  obstructing  the  circu- 
lation by  its  pressure,  while  digitalis  relieves  the  dilatation  of  the  heart. 
In  cases  of  hepatic  dropsy,  caffeine  and  theobromine  have  also  proved 
of  service,  although  here  the  treatment  can  only  be  considered  palliative. 
In  renal  dropsy  theobromine  has  been  used  with  somewhat  variable 
results ;  it  does  not  seem  to  increase  the  albumin  in  the  urine,  but 
not  infrequently  little  or  no  diuresis  follows  its  administration.  This 
is  only  to  be  expected  where  the  renal  cells  are  in  such  a  condition  as 
to  be  incapable  of  stimulation.  Where  the  disease  is  less  developed 
the  members  of  this  series  produce  the  usual  increase  in  the  se- 
cretion. 

Inflammatory  effusions  do  not  seem  to  be  lessened  to  any  marked 
extent  by  either  caffeine  or  theobromine. 

Theobromine  in  very  large  doses  has  been  found  to  produce  nausea 
and  loss  of  appetite  when  taken  for  long,  but  in  ordinary  quantities  it 
produces  no  symptoms  save  diuresis.  Theocine  has  undoubtedly  greater 
diuretic  power  than  either  caffeine  or  theobromine,  and  has  been  largely 
advertised  for  the  treatment  of  dropsy.  In  a  large  proportion  of  cases 
it  causes  marked  disturbance  of  the  digestive  organs,  however,  and  in 
several  instances  epileptiform  convulsions  have  followed  its  use. 

A  large  number  of  other  xanthine  derivatives  have  been  formed  and  examined 
experimentally,  but  none  of  them  possesses  any  therapeutic  importance  (Ach, 
Schmiedeberg). 

Coffee  and  Tea. 

Coffee  is  not  used  in  medicine,  but  in  view  of  its  immense  dietetic 
importance  it  may  be  mentioned  here  in  what  respects  it  differs  from 
the  pure  caffeine.  The  coffee  bean  contains  about  f  per  cent,  caffeine, 
and  the  roasting  does  not  seem  to  reduce  the  percentage  at  all,  as  was 
formerly  supposed,  and  since  almost  all  the  caffeine  is  extracted  by  the 
ordinary  culinary  preparation,  a  cup  of  coffee  contains  from  0.1-0.2  G. 


CAFFEINE.  253 

(1J-3  grs.)  of  caffeine.  Along  with  the  caffeine  there  are  extracted  a 
number  of  other  substances,  the  most  important  of  which  are  volatile 
substances,  such  as  furfuralcohol,  produced  by  the  roasting,  which  have 
been  called  Coffeon  and  resemble  in  their  action  the  volatile  oils. 

Tea  contains  a  larger  percentage  of  caffeine  (about  1J-2  per  cent.), 
but  as  less  tea  is  used  than  coffee,  each  cup  may  be  considered  to  con- 
tain 0.1-0.2  G.  (1J-3  grs.).  In  green  tea  there  is  a  considerable 
quantity  of  a  volatile  oil  which  also  passes  into  the  infusion,  but  this 
is  not  present  in  black  tea,  owing  to  the  greater  heat  used  in  its  manu- 
facture. Both  black  and  green  tea  contain  about  7  per  cent,  of  tannic 
acid,  but  this  is  only  extracted  slowly.  The  bitter  taste  in  tea  that 
has  been  prepared  too  long  is  due  to  the  tannic  acid  passing  into  solu- 
tion. 

The  wakeftilness  and  the  relief  from  fatigue  which  are  produced 
by  tea  and  coffee  are  undoubtedly  due  to  the  caffeine  contained  in 
them,  and  are  to  be  ascribed  to  the  central  action  chiefly,  although 
its  action  on  the  muscles  may  also  be  of  some  value  here.  On  the 
other  hand,  the  feeling  of  well-being  and  comfort  produced  by  coffee 
after  a  full  meal  is  probably  to  be  explained  by  the  local  action  of  the 
volatile  oil  in  the  stomach.  The  same  result  is  produced  by  prepara- 
tions of  the  other  volatile  oils,  and,  in  fact,  these  are  often  added  to 
coffee  in  the  form  of  brandy  and  other  liqueurs.  Apart  from  this  local 
action  the  volatile  parts  of  tea  and  coffee  (theon,  coffeon)  seem  to  have 
no  effect  whatever  on  the  economy.  In  experiments  on  the  activity 
of  the  digestive  ferments  outside  the  body,  it  is  found  that  caffeine 
increases  slightly  the  rapidity  of  the  process,  but  that  coffee  and  tea 
retard  it  considerably.  On  the  other  hand,  coffee,  probably  owing  to 
its  volatile  oils,  increases  the  peristaltic  movements  of  the  intestine 
while  caffeine  has  no  effect  on  them.  Tea  that  contains  much  tannic 
acid  precipitates  the  peptones  and  albumins  of  the  stomach,  and  may 
lead  to  chronic  dyspepsia  and  constipation. 

It  was  formerly  stated  that  coffee  lessened  the  tissue  change  and 
that  it  ought  therefore  to  be  included  among  foods,  and  one  enthusiast 
even  suggested  that  a  diet  of  tea  and  coffee  exclusively  should 
be  served  out  in  the  besieged  fortresses  of  France  in  1870.  It  has 
been  shown  conclusively,  however,  that  far  from  lessening  the  metab- 
olism of  the  body,  coffee  and  tea  increase  it,  the  amount  of  urea  and 
carbonic  acid  excreted  being  considerably  augmented  by  their  use. 
This  is  only  to  be  expected  from  the  increased  activity  of  the  nervous 
centres,  which  leads  to  increased  movement  and  increased  consump- 
tion. 

Chocolate  contains  theobromine  (0.5—1  per  cent.),  instead  of  caf- 
feine, and  besides  this  a  large  amount  of  fat  (cacao-butter  30—50  per 
cent.),  starch  and  albumins.  The  theobromine  does  not  possess  the 
stimulant  action  of  caffeine  on  the  nervous  system,  and  chocolate  may 
therefore  be  taken  where  coffee  or  tea  produces  wakefulness.  The 
starch  and  fat  are  assimilated  by  the  tissues  so  that  chocolate  is  a  true 
food.  At  the  same  time  the  cacao-butter  is  not  easily  absorbed  from 


254  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

the  stomach,  and  may  give  rise  to  heaviness  and  discomfort,  and  even 
to  indigestion.  Chocolate  is,  therefore,  often  used  freed  from  the  oil, 
but  theobromine  is  also  somewhat  detrimental  to  the  gastric  mucous 
membrane  after  continued  use. 

BIBLIOGRAPHY. 

Johannsen.     Ueber  die  Wirkungen  des  Koffeins,  Inaug.  Diss.,  Dorpat,  1869. 

Schmiedeberg.  Arch.  f.  exp.  Path.,  ii.,  p.  62.  Ber.  deutsch.  Chem.  Gesellsch.,  xxxiv., 
p.  2550. 

Archangelsky.     Arch,  internal,  de  Pharmacodyn.,  vii.,  p.  405. 

Bock.     Arch.  f.  exp.  Path.,  xliii.,  p.  317. 

Filehne.     Arch.  f.  Anat.  und  Phys.,  1886,  p.  72. 

v.  Schroeder.     Arch.  f.  exp.  Path.,  xxii.,  p.  39  ;  xxiv.,  p.  85. 

Alhanese.     Ibid.,  xxxv.,  p.  449  ;  xliii.,  p.  305.     Bericht.  d.  deutsch.  Chem.  Gesell., 
1899,  p.  2280. 

Bondzynskiu.  Gottlieb.   Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvi.,  p.  45  ;  xxxvii.,  p.  385. 

Heerlein.     Pfl tiger's  Arch.,  Hi.,  p.  165. 

Dreser.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiv.,  p.  221.     Pfliiger's  Arch.,  cii.,  p.  1. 

Sobieranski  and  Modrakowski.     Pfliiger's  Arch.,  xcviii.,  pp.  135,  217. 

Kraepelin.  Ueber  die  Beeinflussung  einfacher  psychischer  Vorgiinge  durch  einige 
Arzneimittel  (Jena,  1892)  and  Psychologische  Arbeiten,  i.,  p.  378  ;  iii.,  p.  203. 

Hellin  u.  Spiro.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxviii.,  p.  368. 

Brunton  and  Cash.     Journ.  of  Phys.,  ix.,  p.  112. 

Lehmann  and  pupils.     Arch.  f.  Hygiene,  xxxii.,  pp.  310,  327  ;  xliv.,  p.  203. 

Erdmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlviii.,  p.  233. 

Miegel.     Congress  f.  inn.  Med.,  1884,  p.  292. 

Pawinsky.     Ztschr.  f.  klin.  Med.,  xxiii.,  p.  440;  xxiv.,  p.  315. 

Fischer.     Ber.  d.  deutsch.  chem.  Gesell.,  xxx.,  p.  549. 

v.   Ftirth.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii.,  p.  389. 

Kriiger.  Bericht.  d.  deutsch.  chem.  Gesell.,  1899,  pp.  2818,  2677,  3336.  Arch.  f. 
exp.  Path.  u.  Pharm.,  xlv.,  p.  259.  Ztschr.  f.  phys.  Chem.,xxi.,  p.  169;  xxxvi., p.  1. 

Ach.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv.,  p.  319. 

Katsuyama.     Ztschr.  f.  phys.  Chem.,  xxxii.,  p.  235. 

Cushny  and  Van  Naten.     Arch,  internat.  de  Pharmacodynamie,  ix.,  p.  169. 

Anten.     Ibid.,  viii.,  p.  455. 

Santesson.     Skandin.  Arch.  f.  Physiol.,  xii.,  p.  259. 

Allard.     Deutsch.  Arch.  f.  klin.  Med.,  Ixxx.     (Theocine.) 

Impens.     Arch,  internat.  de  Pharmacodyn.,  x.,  p.  463.     (Methylanthine.) 

IX.     CURARA. 

Curara,  woorara,  urari  or  woorali,  is  an  arrow  poison  used  by  the 
natives  of  South  America,  who  prepare  it  by  extracting  various  barks 
and  plants.  The  plants  used  seem  to  vary  somewhat  in  different  local- 
ities, but  those  which  produce  the  symptoms  known  as  curara  action 
are  undoubtedly  members  of  the  genus  Strychnos,  such  as  S.  toxifera. 

Different  preparations  of  curara  were  found  by  Boehm  to  contain  different  alka- 
loids. That  formerly  obtainable  owed  its  activity  to  Curarine,  but  the  curara 
now  exported  contains  Tubocurarine,  which  resembles  curarine  in  its  action,  and 
Curine,  a  weaker  poison,  which  has  an  entirely  different  effect.  Another  prepa- 
ration examined  by  him  contained  three  alkaloids,  Protocurine,  Protocuridine  and 
Protocurarine,  the  last  of  which  is  the  most  powerful  of  all  the  curara  alkaloids. 
Most  of  the  experiments  on  which  the  statements  regarding  curara  action  are 
based  were  performed  with  the  crude  drug,  but  the  alkaloids  seem  to  have  a 
very  similar  effect,  with  the  exception  of  curine. 

Action. — The  chief  effect  of  curara  is  paralysis  of  the  Terminations 
of  the  Nerves  Supplying  Striated  Muscle,  and  it  therefore  causes  general 
paralysis  of  all  the  voluntary  movements.  In  the  mammal  the  mus- 


CUEAEA.  255 

cles  give  way  one  after  the  other  until  the  animal  lies  helpless  on  the 
ground.  It  can  still  move  its  limbs,  but  cannot  recover  its  ordinary 
position,  and  soon  the  limbs  become  totally  paralyzed  and  the  respiratory 
movements  alone  persist,  although  they  too  are  slow,  weak  and  jerky. 
Eventually  the  respiration  ceases  also  and  asphyxia  follows,  but  is 
not  betrayed  by  the  usual  convulsions,  owing  to  the  paralysis  of  the 
motor  nerve  ends.  The  blood,  however,  becomes  venous,  and  the  heart 
soon  fails  from  the  asphyxia  and  not  through  the  direct  action  of  the 
poison. 

In  the  frog  similar  symptoms  are  seen,  but  here  the  arrest  of  the 
respiration  is  not  necessarily  fatal,  as  the  skin  carries  on  the  exchange 
of  gases,  and  recovery  not  infrequently  occurs  after  two  or  even  five 
days  of  complete  paralysis.  The  cause  of  the  curara  paralysis  was  dem- 
onstrated by  the  classical  researches  of  Claude  Bernard  and  Kolliker. 
If  the  sciatic  nerve  of  the  frog  be  stimulated  during  the  paralysis  no 
movement  follows,  but  if  the  artery  of  one  leg  be  ligatured  before  the 
application  of  the  poison  this  limb  remains  unparalyzed  and  reacts  to 
reflex  irritation,  while  the  rest  of  the  body  is  perfectly  motionless. 
These  facts  can  only  be  interpreted  in  one  way ;  the  paralysis  is  peri- 
pheral and  not  central,  and  may,  therefore,  be  due  to  action  either  on 
the  muscle,  the  nerve  trunks,  or  the  intermediate  structures.  That 
it  is  not  due  to  the  muscle  is  shown  by  the  fact  that  direct  stimu- 
lation causes  the  same  movement  as  usual.  On  the  other  hand,  in  the 
experiment  in  which  the  artery  is  ligatured,  stimulation  of  the  nerves 
above  the  ligature,  that  is,  where  the  poison  has  access  to  the  nerve 
fibres,  causes  contraction,  so  that  the  nerve  trunks  do  not  seem  affected. 
This  may  be  shown  in  another  way  ;  if  a  nerve-muscle  preparation  be 
made  and  the  nerve  be  laid  in  a  solution  of  curara,  contraction  of  the 
muscle  still  occurs  on  stimulation  of  the  nerve,  but  if  the  muscle  be 
laid  in  the  curara  solution  stimulation  of  the  nerve  has  no  effect  while 
direct  stimulation  still  causes  contraction.  Curara  must,  therefore,  act 
on  the  connection  between  the  nerve  and  muscle  within  the  muscle  it- 
self, that  is,  on  the  terminations  of  the  nerve  in  the  muscle.  Curara 
paralyzes  the  nerve  terminations  without  previous  stimulation. 

Here,  perhaps,  better  than  elsewhere  it  can  be  shown  that  the  condition 
of  ' '  paralysis  ' '  produced  by  poisons  is  analogous  to  that  termed  by  physiol- 
ogists "  fatigue."  It  is  known  that  on  stimulating  a  nerve  rapidly  by  elec- 
tric shocks,  or  otherwise,  the  muscle  at  first  contracts  with  every  stimulation, 
but  eventually  ceases  to  respond,  owing  to  l  i  fatigue ' '  of  the  nerve  ends, 
that  is,  to  their  inability  to  transmit  impulses  from  the  nerve  to  the  muscle. 
If  now  the  response  to  nerve  stimulation  of  a  muscle  to  which  a  minute 
quantity  of  curarine  has  been  applied,  be  compared  with  that  of  a  normal 
one,  it  is  found  that  the  poisoned  one  ceases  to  respond  much  sooner  than 
the  other — i.  e. ,  its  nerve  ends  become  fatigued  much  sooner.  The  more  cu- 
rara is  applied,  the  sooner  does  it  fatigue,  until  at  last  no  response  at  all  can 
be  elicited  from  it.  The  "  paralysis"  of  the  nerve  terminations  by  curara 
then  is  of  the  same  nature  as  physiological  "  fatigue,"  and  other  conditions 
of  "  paralysis  "  are  also  analogous  to  those  produced  by  over-stimulation, 
though  the  exact  condition  of  the  paralyzed  organ  may  not  be  the  same  as  the 
fatigued  one.  Thus  there  is  some  reason  to  suppose  that  in  the  curarized 


256  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

terminations  the  energy  consumed  in  transmission  is  present,  but  in  such  a 
form  that  it  cannot  be  changed  to  actual  movement,  while  in  fatigue  the 
energy  has  all  been  exhausted  by  the  impulses  which  have  already  passed 
through. 

Curara  paralyzes  very  readily  the  terminations  of  nerves  in  all  striped 
muscular  tissue  except  the  heart.  The  nerves  first  affected  are  those 
of  the  short  muscles  of  the  toes,  ear  and  eye,  later  those  supplying 
the  limbs,  head  and  neck,  and,  last  of  all,  those  supplying  the  muscles 
of  respiration.  At  first,  slight  movements  can  be  performed,  because 
single  impulses  can  pass  through  the  nerve  ends,  but  sustained  con- 
tractions such  as  are  necessary  to  preserve  the  equilibrium,  cannot  be 
maintained,  and  the  animal  therefore  falls.  The  intermittent  impulses 
to  the  respiratory  muscles  still  allow  time  in  the  interval  for  the  re- 
covery of  the  terminations,  but  as  the  intoxication  proceeds,  the  num- 
ber of  impulses  which  can  pass  through  becomes  fewer  and  fewer,  and 
the  movement  therefore  assumes  more  and  more  the  character  of  a  jerk. 
Eventually  total  paralysis  sets  in  and,  unless  artificial  respiration  is 
carried  on,  asphyxia  follows.  Small  doses  of  curara  do  not  affect  the 
inner vation  of  unstriped  muscle,  and  the  strict  demarcation  of  its  action 
is  seen  very  distinctly  in  organs  which  consist  partly  of  striated  and 
partly  of  unstriated  fibres.  Thus  in  the  oesophagus,  the  striated  muscle 
fibres  no  longer  contract  on  stimulation  of  the  vagus  after  curara, 
while  the  unstriated  continue  to  respond  as  usual.  In  the  iris  of  the 
mammals,  which  consists  of  unstriated  muscle,  curara  has  no  effect,  while 
the  striated  muscle  of  the  bird's  iris  ceases  to  respond  to  stimulation  of 
the  motor  oculi,  but  contracts  on  direct  stimulation.  The  terminations 
of  the  nerves  in  the  heart  are  not  affected,  as  the  cardiac  fibre  is  not  of 
the  same  character  as  the  ordinary  striated  one,  but  the  nerves  of  the 
lymph  hearts  of  the  frog  are  paralyzed,  these  organs  consisting  of  ordi- 
nary striated  muscle.  Curiously  enough,  it  has  been  found  that  curara 
does  not  act  on  the  terminations  of  the  motor  nerves  supplying  the  elec- 
trical organ  of  the  torpedo,  although  this  organ  is  analogous  to  striated 
muscle  in  many  respects.  The  nerve  ends  in  striated  muscle  in  in- 
vertebrates also  appears  to  be  immune  to  curara  (Straub). 

The  nerve  fibres  seem  unaffected  by  curara,  for  stimulation  causes 
the  usual  electrical  changes  in  them  after  it.  The  action  of  curara  on 
the  muscle  fibres  has  been  a  good  deal  disputed,  many  authorities  deny- 
ing that  any  alteration  whatsoever  occurs,  while  others  assert  that  slight 
modifications  may  be  observed. 

When  larger  quantities  of  curara  or  curarine  are  injected,  several 
other  organs  are  affected.  Thus  the  Peripheral  Ganglia  cease  to  trans- 
mit impulses,  and  hence  stimulation  of  the  nerves  central  to  them  has 
little  or  no  effect.  In  this  way  the  stimulation  of  the  vagus  in  the 
neck  produces  no  slowing  of  the  heart,  because  the  impulses  can  no 
longer  pass  through  the  ganglionic  structures  on  the  course  of  the 
fibres,  and  stimulation  of  several  secretory  nerves,  such  as  the  chorda 
tympani,  has  no  effect  on  the  secretion.  The  sympathetic  ganglia  are 
also  paralyzed  by  nicotine,  which  differs  from  curara  in  stimulating 


CURARA.  257 

them  previously,  and  also  in  attacking  the  ganglia  before  it  affects  the 
endings  in  muscle. 

Large  quantities  of  curara  are  often  said  to  paralyze  the  nerve 
terminations  in  unstriated  muscle,  but  this  has  never  been  satisfactorily 
proved,  all  the  symptoms  quoted  to  show  this  effect  being  explained 
by  the  paralysis  of  the  sympathetic  ganglia,  which  undoubtedly  occurs. 

Curara,  then,  first  paralyzes  the  terminations  of  efferent  or  centri- 
fugal nerves  in  voluntary  muscle,  and  in  larger  quantities  the  ganglia 
(c£  Nicotine).  The  peripheral  terminations  of  the  afferent  or  sensory 
nerves  seem  unaffected,  for  if  the  artery  of  one  leg  be  ligatured  before 
the  application  of  curara,  reflex  movements  may  be  obtained  in  it  from 
stimulation  of  any  part  of  the  body,  while  if  the  sensory  terminations 
were  paralyzed  reflexes  could  be  elicited  only  by  the  irritation  of  parts 
to  which  the  poison  had  not  penetrated,  i.  e.,  from  the  ligatured  leg. 

Very  large  quantities  of  curarine  are  said  by  Tillie  to  cause  a  stim- 
ulation of  the  Central  Nervous  System  resembling  that  described  under 
strychnine.  In  ordinary  poisoning,  however,  no  evidence  of  this 
stimulation  is  shown,  as  although  an  increased  number  of  impulses 
may  be  sent  out,  they  cannot  reach  the  peripheral  organs  owing  to  the 
paralysis  of  the  motor  end-plates  and  of  the  ganglia. 

The  Heart  does  not  seem  to  be  acted  on  directly  by  ordinary  quan- 
tities of  curarine,  and  the  circulation  is  left  intact  long  after  the 
respiratory  nerves  have  been  paralyzed.  Large  quantities  prevent 
the  inhibitory  action  of  the  vagus,  and  the  pulse  is  consequently 
quickened,  but  the  blood-pressure  often  begins  to  fall  at  the  same  time, 
owing  to  the  dilatation  of  the  peripheral  arteries  through  paralysis  of 
the  ganglia  on  the  course  of  the  constrictor  nerves.  After  curara  and 
curarine  the  movements  of  the  Intestines  are  said  to  be  increased. 
This  was  formerly  supposed  to  be  due  to  the  asphyxia,  but  seems  to 
be  independent  of  it,  for  the  increased  peristalsis  occurs  even  when 
artificial  respiration  is  kept  up,  and,  according  to  Nasse,  the  irritability 
of  the  bowel  muscle  is  much  increased  by  curara.  A  similar  accelera- 
tion of  the  rhythmic  movements  of  the  spleen  has  been  noted  after 
curara  by  Shafer  and  Moore. 

The  Secretions  sometimes  seem  to  be  increased  by  curara,  for  tears, 
saliva  and  perspiration  may  be  formed  in  considerable  excess  of  the 
rormal. 

Metabolism. — The  cessation  of  the  ordinary  movements  after  curara 
and  under  artificial  respiration  has  generally  been  accompanied  by  a 
marked  decrease  in  the  oxygen  absorption  and  the  carbonic-acid  excre- 
tion, but  Frank  and  Gebhard  state  that  this  is  not  the  case  when  the 
temperature  is  maintained  by  the  application  of  heat.  Sugar  and  lactic 
acid  are  often  found  in  the  urine  after  curara,  but  this  is  due  to  partial 
asphyxia  and  not  to  the  direct  action  of  the  poison  ;  the  glycogen  of 
the  liver  and  muscles  disappears  from  the  same  cause. 

Curara  is  excreted  by  the  kidneys  apparently  unchanged.     It  has 
long  been  known  that  this  arrow  poison  may  be  swallowed  with  impu- 
nity, provided  there  is  no  wounded  surface  in  the  mouth  or  throat  and 
17 


258  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

that  it  is  therefore  perfectly  safe  to  suck  the  poison  from  a  wound. 
This  has  been  explained  in  various  ways,  some  holding  that  the  ab- 
sorption from  the  stomach  is  so  slow  that  the  kidneys  are  able  to  ex- 
crete the  poison  as  fast  as  it  reaches  the  blood  and  that  this  prevents  its 
accumulation  in  sufficient  quantity  to  affect  the  tissues.  Others  suppose 
that  the  liver  retains  and  destroys  it  and  a  third  view  is  that  it  is  ren- 
dered innocuous  in  passing  through  the  stomach  walls. 

Rothberger  has  recently  shown  that  curara  and  physostigmine  are 
mutually  antagonistic  so  far  as  the  action  on  the  nerve  terminations  in 
striated  muscle  is  concerned  (see  Physostigmine). 

Curine,  the  second  alkaloid  found  by  Boehm  in  some  specimens  of  curara, 
is  a  much  less  poisonous  body  than  curarine.  It  possesses  some  action  on 
the  heart,  the  same  appearances  following  its  injection  in  the  frog  as  after 
digitalin  and  veratrine,  while  in  mammals  the  rhythm  is  slow  even  after 
paralysis  of  the  inhibitory  mechanism. 

PREPARATIONS. 

Curara,  an  extract  of  varying  constitution  and  strength.  The  active  con- 
stituents are  freely  soluble  in  acidulated  water,  and  when  used  ought  to  be 
injected  hypodermically.  Before  using  curara  in  therapeutics  it  is  always 
necessary  to  estimate  the  strength  of  the  preparation  by  experiments  on 
animals,  and  its  application  ought  to  be  graduated,  commencing  with  the 
smallest  quantities  and  increasing  them  until  the  desired  effect  is  attained. 
Neither  curara  nor  its  alkaloids  are  official. 

Therapeutic  Uses. — Curara  has  been  used  occasionally  in  various  condi- 
tions of  exaggerated  movement,  such  as  tetanus,  strychnine  poisoning  and 
hydrophobia.  The  object  is  to  lessen  the  movement  by  partial  paralysis  of 
the  motor  terminations.  The  respiratory  nerves  being  the  last  to  be  affected 
by  the  poison,  the  convulsions  may  be  controlled,  or  at  any  rate  hindered 
from  causing  such  marked  irregularity  of  the  respiration  as  they  would 
otherwise  do,  and  in  the  same  way  the  overstrain  of  the  heart  caused  by  the 
convulsions  may  be  prevented.  The  danger  accompanying  the  use  of  curara 
is  great,  however,  and  the  fact  that  in  all  these  cases  the  cause  of  the  move- 
ment is  excessive  activity  of  the  central  nervous  system  would  seem  to  indi- 
cate one  of  the  many  depressants  of  that  system,  rather  than  a  drug  such  as 
curara,  whose  action  is  on  an  entirely  different  part  of  the  body.  Some 
cases  of  tetanus  and  one  of  hydrophobia  are  alleged  to  have  been  successfully 
treated  by  it,  but  its  use  must  still  be  regarded  as  purely  experimental,  and, 
in  fact,  as  generally  opposed  to  the  teachings  of  rational  therapeutics. 

Paralysis  of  the  terminations  of  the  motor  nerves  in  striated  muscle — the 
so-called  "  Curara- Action  " — is  elicited  by  a  large  number  of  poisons,  but  in 
few  of  them  is  it  the  first  effect  of  their  application.  Many  drugs  induce  it 
only  when  injected  in  large  quantities  and  at  the  end  of  a  series  of  phenom- 
ena produced  by  their  action  on  other  parts  of  the  body  ;  it  is  observed  much 
more  frequently  in  frogs  than  in  mammals,  and  is  often  of  little  importance 
compared  to  the  other  symptoms.  Among  the  bodies  which  resemble  curara 
more  closely  in  their  action,  the  peripheral  paralysis  playing  the  chief  role 
in  their  effects,  are  the  ammonium  compounds  formed  from  the  natural  alkaloids 
by  the  substitution  of  an  alkyl,  e.  g.,  methylstrychnine,  amyl quinine,  etc.1 
Some  of  the  ammonium  salts  and  many  of  the  alkyl  ammonium  combinations 
also  cause  it,  so  that  the  general  statement  may  be  made  that  quaternary 

1  Boehrn  has  recently  stated  that  tubocurarine,  which  is  the  active  constituent  of 
much  of  the  modern  curara,  is  really  one  of  those  methyl  bases  (methylcurine). 


CONIINE,    GELSEMININE  AND  SPARTEINE.  259 

compounds  of  nitrogen  possess  a  curara  action  ;  in  these  the  nitrogen  atom 
may  be  replaced  by  phosphorus  or  arsenic  without  loss  of  the  curara  action, 
so  that  nitrogen  is  not  a  necessary  constituent  of  substances  possessing  this 
property.  The  simpler  bodies,  pyridine  and  quinoline  which  form  the  basis 
of  most  of  the  natural  alkaloids,  have  little  action  save  on  the  nerve  ends,  a 
fact  wThich  is  of  some  importance  in  the  consideration  of  the  relation  between 
the  chemical  constitution  and  the  pharmacological  action  of  poisons.  At 
the  same  time  the  property  of  causing  this  paralysis  is  so  widespread  among 
substances  of  very  different  constitution  that  it  may  be  looked  upon  as  in- 
dicating a  peculiar  susceptibility  and  weakness  of  the  motor  terminations, 
more  especially  in  the  lower  vertebrates,  and  inferences  based  upon  it  as  to 
the  mutual  relation  of  substances  are  to  be  received  with  caution  (San- 
tesson). 

BIBLIOGRAPHY. 

Cl.  Bernard,     Comptes  rendus,  xxxi.,  p.  533;  xliii.,  p.  825. 

Kolliker.     Virchow's  Archiv,  x.,  p.  3. 

Boehm.     Beitrage  zur  Physiologie  C.  Ludwig  zu  seinem  sechzigsten  Geburtstage 
gewidmet,  Leipzig,  1887,  p.  173.     Arch,  der  Pharmacie,  ccxxxv.,  p.  660. 

Overend.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi.,  p.  1. 

Tillie.     Ibid.,  xxvii.,  p.  1. 

Boehm.     Ibid.,  xxxv.,  p.  16. 

Santcsson.     Ibid.,  xxxv.,  p.  23.     Skand.  Arch.  f.  Physiol.,  x.  and  xi. 

Saner.     Pfluger's  Arch.,  xlix.,  p.  423. 

Nikokki  u.  Dogiel     Ibid.,  xlvii.,  p.  68. 

Jakabhazy.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiii.,  p.  10. 

Morishima.     Ibid.,  p.  28. 

Straub.     Pfluger's  Arch.,  Ixxix.,  p.  379. 

Meyer.     Ergebnisse  der  Physiol.,  i.  (2),  p.  200. 

Frank  and  Gebhard.     Ztschr.  f.  Biol.,  xliii.,  p.  117. 


X.     CONIINE,    GELSEMININE   AND   SPARTEINE. 

Several  alkaloids  which  show  many  points  of  resemblance  to  curara 
in  their  pharmacological  effects,  may  be  classed  together,  although  their 
action  may  diifer  in  details. 

Coniine. 

Coniine  is  one  of  the  simpler  derivatives  of  Piperidine,  which  is 
obtained  from  Pyridine  by  reduction.  A  series  of  alkaloids  may  be 
formed  from  piperidine  by  substituting  methyl,  ethyl,  propyl  or  other 
alkyls  for  hydrogen,  and  one  of  these,  a-propyl-piperidine,  is  the 
natural  alkaloid  coniine. 

Pyridine.  Piperidine.  Coniine. 

CH  CH  CH 


NH  NH 


Coniine  is  found  in  Hemlock  (Conium  maculatum),  along  with  two 
nearly  allied  alkaloids,  Methyleoniine  and  Conhydrine.  The  latter  dif- 
fers from  coniine  only  in  having  a  hydroxyl  group  in  the  side  chain. 
Methyleoniine  is  found  in  many  specimens  of  coniine,  and  is  probably 
formed  in  the  plant,  although  this  has  not  been  definitely  proved ;  in 


260  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

it  the  hydrogen  attached  to  the  nitrogen  of  coniine  is  replaced  by 
methyl.  Coniine  is  of  some  historical  importance,  as  the  first  vegetable 
alkaloid  which  was  successfully  formed  by  synthesis  in  the  laboratory. 
It  is  a  volatile  fluid,  characterized  by  a  strong  mouse-like  odor,  but 
forms  crystalline,  non-volatile  salts.  The  two  other  alkaloids  of  hem- 
lock act  in  the  same  way  as  coniine,  although  much  more  weakly,  so 
that  the  effects  of  the  crude  preparations  of  the  plant  are  identical 
with  those  of  coniine. 

Piperidine  and  its  compounds  with  methyl  and  ethyl-act  in  the  same 
way  as  coniine  but  more  weakly.  An  ascending  scale  of  toxicity  may 
be  formed,  commencing  with  piperidine  and  passing  upwards  through 
methyl-  and  ethyl-piperidine  to  coniine.  The  other  simple  derivatives 
of  piperidine  seem  to  resemble  coniine  in  their  action  as  far  as  it  has 
been  investigated. 

Symptoms.  —  The  general  symptoms  induced  in  man  by  poisonous 
doses  of  coniine  are  weakness,  languor  and  drowsiness  which  does  not 
pass  into  actual  sleep.  The  movements  are  weak  and  unsteady,  the 
gait  is  staggering,  and  nausea  and  vomiting  generally  set  in,  along  with 
profuse  salivation.  In  most  cases  the  intelligence  remains  clear  to  the 
end,  as  is  related  of  the  death  of  Socrates  from  hemlock  poisoning, 
but  in  some  instances  imperfect  vision  and  hearing  have  been  noted. 
The  pupils  are  somewhat  dilated.  Tremors  and  fibrillary  contractions 
of  the  muscles  are  often  seen  in  animals,  and  some  observers  state  that 
actual  convulsions  occur.  The  breathing  becomes  weaker  and  slower 
and  death  occurs  from  its  arrest. 

Action.  —  Coniine  is  sometimes  credited  with  possessing  a  narcotic 
depressant  action  on  the  Central  Nervous  System,  but  this  is  by  no 
means  a  characteristic  feature  in  poisoning,  for  in  both  man  and 
animals  consciousness  is  often  retained  until  immediately  before  the 
cessation  of  the  respiration.  Other  writers  mention  convulsions  as  a 
feature  of  coniine  poisoning,  and  weak  convulsive  movements  are  often 
seen  before  death,  obviously  from  the  failure  of  the  respiration. 
Quite  distinct  from  these  are  the  twitching  and  tremors  of  the  earlier 
stages  of  the  intoxication,  which  are  often  accompanied  by  a  certain 
stiffness  and  rigidity  of  some  of  the  muscles  of  the  limbs.  Some  of 
these  movements  may  be  due  to  the  partial  paralysis  of  the  motor 
nerve  terminations  preventing  the  animal  from  contracting  its  mus- 
cles in  a  normal  tetanus  and  permitting  only  of  short,  jerky  move- 
ments, which  may  readily  be  mistaken  for  convulsions.  But  at  the 
same  time,  the  tremor  and  the  rigidity  of  the  limbs  seem  to  indicate 
some  central  stimulation,  although  this  point  requires  further  investi- 
gation. This  preliminary  stimulation  may  afterwards  pass  into  de- 
pression of  the  lower  parts  of  the  central  nervous  system,  although  this 
is  denied  by  some  investigators,  who  maintain  that  coniine  has  little 
or  no  central  action,  but  manifests  its  activity  only  in  the  peripheral 
organs. 

Coniine  causes  nausea  and  very  often  vomiting  at  an  early  stage  of 
its  action.  This  may  be  elicited  by  its  hypodermic  or  intravenous  in- 


CONIINE.  261 

jection,  and  is  probably  due  to  an  alteration  in  the  medullary  centres 
rather  than  in  the  stomach.  The  nausea  is  accompanied  by  profuse 
salivation  and  sometimes  by  perspiration. 

The  chief  effect  of  coniine  in  the  frog  is  a  paralysis  of  the  Termina- 
tions of  the  Motor  Nerves  similar  to  that  induced  by  curara.  This 
paralysis  is  elicited  only  with  difficulty  in  the  mammal,  but  unques- 
tionably occurs  to  a  more  or  less  marked  extent.  According  to  some 
researches  on  the  subject,  all  the  symptoms  in  mammals  are  due  to  the 
paralysis  of  the  ends  of  the  motor  nerves,  while  others  regard  both  the 
convulsions  and  the  final  failure  of  the  respiration  as  of  central  origin. 
It  seems  likely  that  while  in  the  frog  the  symptoms  are  all  due  to  the 
action  on  the  nerve  terminations,  some  of  the  phenomena  observed  in 
mammals  are  due  to  central  stimulation  and  to  subsequent  paralysis  of 
the  medullary  centre  of  respiration.  It  is  difficult  to  explain  on  any 
other  theory  how  the  symptoms  of  coniine  poisoning  are  so  different 
from  those  of  curara. 

Coniine  acts  on  the  Peripheral  Ganglia  in  the  same  way  as  curara. 
According  to  some  writers  these  are  first  stimulated  and  then  para- 
lyzed, and  there  seems  to  be  no  question  as  to  the  final  paralysis, 
whether  the  preliminary  stimulation  is  present  or  not.  Coniine  cer- 
tainly does  not  act  so  strongly  on  the  ganglia  as  nicotine,  and  the 
details  of  the  action  may,  therefore,  be  left  for  discussion  under  that 
heading.  (See  page  274.)  The  inhibitory  impulses  no  longer  reach 
the  heart  after  large  doses  of  coniine,  owing  to  paralysis  of  the  gang- 
lionic  apparatus  and  stimulation  of  the  vagus  nerve  has  no  effect  on 
the  pulse  rate.  Some  drugs  which  act  on  the  extreme  terminations  of 
the  inhibitory  fibres  still  slow  and  weaken  the  heart,  however.  Simi- 
larly, stimulation  of  the  cervical  sympathetic  no  longer  dilates  the 
pupil,  because  the  superior  cervical  ganglion  is  paralyzed.  The  partial 
dilatation  of  the  pupil  in  cases  of  poisoning  may,  perhaps,  indicate  a 
similar  action  on  the  ciliary  ganglion. 

Coniine  seems  to  have  but  little  direct  effect  on  the  Heart  though 
large  quantities  slow  the  rhythm  and  somewhat  prolong  the  systole  in 
the  frog  (Moore  and  Row),  and  some  slowing  of  the  mammalian  heart 
has  been  noted  from  the  intravenous  injection  of  large  quantities.  The 
inhibitory  mechanism  is  often  found  to  be  stimulated  and  the  pulse  is 
accordingly  somewhat  slow  and  weak.  The  paralysis  of  the  ganglia 
on  the  inhibitory  nerve  may  lead  to  some  acceleration  in  other  cases, 
but  the  changes  in  the  heart  are  not  marked  features  in  the  intoxica- 
tion. 

Moore  and  Row  have  observed  a  very  considerable  though  transient 
increase  in  the  arterial  tension  after  coniine,  and  regard  it  as  of  pe- 
ripheral origin,  for  they  found  that  the  perfusion  of  coniine  through 
the  blood  vessels  of  the  frog  tends  to  constrict  them,  while  the  direct 
application  to  the  exposed  blood  vessels  has  no  such  effect,  but  rather 
widens  their  calibre.  They  are  accordingly  inclined  to  regard  the  rise 
of  blood-pressure  as  due  to  a  stimulation  of  the  ganglionic  apparatus 
lying  on  the  course  of  the  vaso-constrictor  nerves. 


262  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

The  Respiration  is  generally  accelerated  and  deepened  in  the  earlier 
stages  of  the  coniine  intoxication,  but  later  becomes  slow  and  labored, 
then  weak  and  irregular,  and  finally  ceases  while  the  heart  is  still  strong 
and  the  consciousness  has  just  disappeared.  The  cause  of  the  asphyxia 
is  still  undecided,  many  investigators  holding  that  the  centre  is  paralyzed 
before  the  terminations  of  the  nerves  in  the  diaphragm,  while  the  ma- 
jority of  recent  investigators  look  upon  the  paralysis  of  those  termina- 
tions as  the  cause  of  death. 

A  curious  change  has  been  observed  by  Giirber  in  the  Blood  Cells  of 
frogs  poisoned  with  coniine.  Numerous  small  vacuoles  appear  in  the 
red  corpuscles,  and  persist  long  after  the  frog  shows  no  further  symp- 
toms of  poisoning.  The  nucleus  is  also  somewhat  altered,  but  not  so 
characteristically. 

Coniine  is  rapidly  excreted  in  the  urine,  so  that  its  action  passes  off 
very  soon  even  when  quite  large  doses  are  taken.  The  treatment  of 
coniine  poisoning  therefore  consists  in  evacuation  of  the  stomach  and 
artificial  respiration. 

Piperidine  acts  in  the  same  way  as  coniine,  but  more  weakly,  while 
methyl-  and  ethyl-piperidine  stand  between  them  in  toxicity..  Many 
of  the  piperidine  alkaloids  cause  the  formation  of  vacuoles  in  the  red 
blood  cells  of  the  frog,  and  the  simpler  members  of  the  series  act  more 
strongly  in  this  direction  than  the  more  complex  ones,  while  they  are 
much  less  active  as  general  poisons. 

Pyridine  resembles  piperidine  in  most  features  but  does  not  paralyze 
the  ganglia  nor  increase  the  blood-pressure.  It  seems  more  poisonous 
in  frogs,  and  induces  distinct  depression  of  the  central  nervous  system, 
but  like  piperidine  it  is  only  feebly  poisonous  in  mammals.  Pyridine 
is  excreted  in  the  urine  as  methyl-pyridine,  a  combination  between  it 
and  the  alkyl  occurring  in  the  tissues.  A  similar  synthesis  occurs 
between  methyl  and  telluric  acid  (see  Tellurium). 

Quinoline  and  isoquinoline  cause  in  mammals  a  condition  of  col- 
lapse similar  to  that  seen  under  the  antipyretics  and  the  benzol  com- 
pounds. 

PEEPAEATIONS. 

Conium  (U.  S.  P.),  Conii  Fructus  (B.  P.),  the  dried,  full-grown,  unripe 
fruit  of  Conium  maculatum,  or  hemlock. 

Fluidextractum  Conii  (U.  S.  P.),  0.1-0.5  c.c.  (2-8  mins.). 

Tinetura  Conii  (B.  P.),  £-1  fl.  dr. 

Conii  Folia  (B.  P.),  the  fresh  leaves  and  young  branches  of  Conium  mac- 
ulatum, collected  when  the  fruit  begins  to  form. 

Succus  Conii  (B.  P.),  juice  of  hemlock,  in  which  one  part  of  alcohol  is 
added  to  three  of  the  juice,  1-2  fl.  drs. 

Unguentum  Conii  (B.  P.). 

Therapeutic  Uses.  —  Conium  has  passed  into  almost  complete  disuse, 
It  has  been  prescribed  in  whooping-cough  and  chorea  with  doubtful 
results,  and  has  been  employed  locally  and  given  internally  to  relieve 
pain.  Tetanus  and  strychnine  poisoning  have  been  treated  with  it 
without  apparent  results. 


GELSEMIUM.  263 


BIBLIOGRAPHY. 


Guttmann.     Berl.  klin.  Woch.,  1866,  p.  45. 

Kolliker.     Virchow's  Arch.,  x.,  p.  235. 

Prevost.     Arch,  de  Physiol.  (2),  vii.,  p.  40. 

Boehm.     Arch.  f.  exp.  Path.  u.  Pharm.,  xv.,  p.  432. 

Hayashi  and  Muto.     Ibid.,  xlviii.,  p.  356. 

Gurber.     Arch.  f.  Anat.  und  Phys.,  1890,  p.  401. 

Cushny.     Journ.  of  Exp.  Med.,  i.,  p.  202. 

Moore  and  Row.     Journ.  of  Phys.,  xxii.,  p.  273. 

Stockman.     Journ.  of  Phys.,  xv.,  p.  245. 

Bruntonand  Tunnicliffe.     Ibid.,  xvii.  ,  p.  272. 

Heinz.     Virchow's  Arch.,  cxxii.,  p.  116. 

His.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxii.,  p.  253. 

Cohn.     Zts.  f.  phys.  Chem.,  xviii.,  p.  112  ;  xx.,  p.  210. 


Gelsemium  semper  virens  (Yellow  Jasmine  or  Carolina  Jasmine) 
contains  two  alkaloids,  Gelsemine  and  Gelseminine.1  Gelsemine  forms 
crystalline  salts,  while  gelseminine  is  entirely  amorphous,  and,  as  far  as 
is  known,  does  not  form  any  crystalline  combinations.  Gelsemine  is 
only  slightly  active,  inducing  the  same  symptoms  in  frogs  as  strych- 
nine, but  having  no  effects  on  mammals,  even  when  injected  into  a  vein 
in  very  large  quantity.  Gelseminine,  on  the  other  hand,  is  a  powerful 
poison  which  resembles  coniine  in  most  of  its  effects.  The  action  of 
the  crude  preparations  of  gelsemium  is  undoubtedly  due  to  gelsemi- 
nine and  not  to  gelsemine,  as  far  as  mammals  are  concerned.  Large 
quantities  of  the  extract  injected  into  frogs  may,  however,  increase 
the  reflex  movements  somewhat  from  the  gelsemine  they  contain. 

Action.  —  The  symptoms  of  gelsemium  poisoning  resemble  those  of 
coniine  so  closely  that  the  reader  may  be  referred  to  the  description 
given  under  the  latter.  Grelseminine  differs  from  coniine  chiefly  in 
possessing  a  more  depressant  action  on  the  central  nervous  system.  In 
the  frog  the  spinal  cord  is  distinctly  less  active  than  usual  before  the 
ends  of  the  motor  nerves  are  paralyzed,  and,  in  fact,  the  depression  of 
the  central  nervous  system  seems  to  be  the  cause  of  the  general 
paralysis  in  these  animals,  rather  than  the  peripheral  action,  although 
this  is  always  present.  In  mammals  the  symptoms  resemble  those 
of  coniine  more  closely  than  in  the  frog,  and  there  may  be  some  ques- 
tion as  to  whether  the  effects  are  mainly  central  or  peripheral  in  ori- 
gin. There  is  a  general  consensus  of  opinion,  however,  amongst  those 
who  have  worked  on  the  subject,  that  gelseminine  proves  fatal  by  para- 
lyzing the  respiratory  centre  rather  than  the  terminations  of  the  nerves 
in  the  diaphragm  and  other  muscles,  while  most  writers  now  consider 
the  asphyxia  of  coniine  poisoning  due  to  the  peripheral  action.  The 
symptoms  are  practically  identical,  however,  and  it  will  probably  be 
found  that  both  act  on  the  same  points  in  the  innervation  of  the  respi- 
ration. In  the  meantime  the  question  must  remain  undecided  for 
both  poisons. 

The  pupil  is  very  widely  dilated  by  gelseminine  when  a  solution  is 

1  Gelsemine  is  frequently  known  as  gelseminine,  a  use  of  the  term  which  leads  to 
some  confusion,  and  which  is  not  based  on  the  history  of  the  drug. 


264  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

applied  locally  to  the  eye,  much  less  so  in  general  poisoning,  in  which 
the  respiration  generally  fails  before  the  pupil  is  fully  dilated.  The 
power  of  accommodation  is  also  entirely  lost  when  gelseminine  or  gel- 
semium  tincture  is  applied  to  the  eye.  This  mydriatic  effect  has  not 
been  explained,  but  the  most  plausible  suggestion  would  seem  to  be 
that  gelseminine  paralyzes  the  terminations  of  the  oculomotor  nerve  in 
the  eye  in  the  same  way  as  atropine.  Gejs^mjmne  differs  from  atro- 
pine  in  its  behavior  to  other  nerves,  however,  for  it  paralyzes  the  inlrib- 
jtojrv  cardiac  fibres  and  the  chorda  tympam  through  acting  on  tne  gan- 
gliomc^siniotrires  on  their  course  and  nof  on  the  extreme  terminations. 
Its  action  oiyiie^ganiglia,  as  far  as  it  is  known,  resembles  that  of  coniine, 
but  it  does  not  cause  "any  increase  in  the  arterial  tension,  such  as  is 
observed  under  this  poison. 

PREPARATIONS. 

Gelsemium  (U.  S.  P.),  Gelsemii  Radix  (B.  P.),  the  dried  rhizome  and 
roots  of  Gelsemium  sempervirens  or  nitidum. 

Fluidextractum  Gelsemii  (  U.  S.  P.),  0.3-0.6  c.c.  (5-10  mins.). 

Timtura  Gelsemii  (U.  S.  P.,  B.  P.),  0.3-1  c.c.  (5-15  mins.). 

"  Gelsemine  "  is  an  unofficial  mixture  of  the  alkaloids  in  very  varying  pro- 
portions. In  some  preparations  no  gelseminine  whatever  was  found. 

Therapeutic  Uses.  —  The  tincture  of  gelsemium  has  been  employed  as 
a  nr^driatic  in  ophthalmology,  but  it  presents  no  advantages  over  the 
more  generally  used  preparations  of  atropine,  and  sometimes  causes 
some  pain  and  redness,  which  has  prevented  its  general  adoption  for 
this  purpose.  In  certain  forms  of  ngyxajgja,  especially  of  the  facial 
branches  of  the  trigeminus,  gelsemium  has  proved  of  some  value,  when 
administered  internally  as  the  tincture. 

BIBLIOGRAPHY. 

Ringer  and  Murrell.     Lancet,  1876,  i.,  p.  82. 

Putzeys  and  Romiee.  Memoire  sur  1'  action  physiologique  de  la  Gelsemine.  Bruxelle, 
1878. 

Cushny.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi.,  p.  49. 

Sparteine^ 

Another  alkaloid  which  resembles  coniine  closely  in  its  action  is 
Sparteine,  which  is  found  in  the  common  broom  plant  (Spartium  or 
Cytisus  scoparius),  along  with  a  neutral  substance,  Scoparin.  Spar- 
teine *  is  a  pyridine  derivative  possessing  the  formula  C15H26N2,  and 
is  a  fluid,  but  forms  crystalline  salts,  which  are  often  prescribed  instead 
of  the  crude  preparations. 

Action. — The  general  effects  of  sparteine  are  almost  identical  with 
those  of  coniine,  but  it  seems  very  probable  that  the  central  nervous 
system  is  little  affected  by  it,  the  whole  of  the  phenomena  pointing  to 
a  paralysis  of  the  peripheral  terminations  of  the  motor  nerves  and 
probably  of  the  terminations  around  the  cells  of  the  sympathetic  gan- 
glia. Sparteine  has  more  effect  than  coniine  on  the  heart,  which  it 
1  Sparteine  also  occurs  in  the  black  and  yellow  lupines  along  with  lupinine. 


SPAtiTEtNE.  265 

[epresses   so  that   the  rhythm  is   slow  and   the    contractions   weak.  I 
len  injected  into  a  vein,  sparteine  induces  less  increase  in  the  arterial! 

jsion  than  coniine,  probably  because  the  contraction  of  the  vessels! 

counterbalanced  by  the  weakness  of  the  heart.     No  increase  in  the' 
arterial  tension  is  observed  from  the  administration  of  sparteine  inter- 
nally, and  even  the  slight  rise  of  pressure  induced  by  intravenous  in- 
jection is  of  only  short  duration. 

The  slow  pulse  and  slight  rise  of  pressure  observed  in  experiments 
in  animals  when  sparteine  is  injected  intravenously,  have  led  some 
writers  to  ascribe  to  it  an  action  similar  to  that  of  digitalis,  and  at 
one  time  sparteine  was  used  to  some  extent  as  a  substitute  for  the 
latter ;  both  experimental  and  clinical  observations,  however,  go  to 
show  that  these  claims  are  quite  unfounded,  and  sparteine  is  compara- 
tively little  used  at  the  present  time,  and  possesses  no  properties  which 
are  likely  to  reinstate  it  in  favor. 

Sparteine  is  very  much  less  poisonous  than  either  coniine  or  gelsemi- 
nine.  It  proves  fatal  to  animals  by  paralyzing  the  terminations  of  the 
phrenic  nerves  in  the  diaphragm. 

Broom  tops  have  long  enjoyed  a  certain  reputation  as  a  diuretic,  and 
this  perhaps  strengthened  the  belief  in  the  virtues  of  sparteine  as  a 
heart  remedy.  The  diuresis  is  not  due  to  the  sparteine,  however, 
but  to  the  scoparin,  which  seems  to  act  on  the  renal  epithelium  in  the 
same  way  as  Uva-ursi  and  other  remedies  of  that  series.  The  broom 
tops  are  generally  administered  in  the  form  of  a  decoction  or  infusion, 
and  the  large  amount  of  water  taken  along  with  them  may  also  tend 
to  increase  the  urine  and  to  strengthen  the  reputation  of  the  remedy. 

PREPARATIONS. 

Scoparius  (U.  S.  P.),  Scoparii  Cacumina  (B.  P.),  the  tops  of  Cytisus  sco- 
parius  or  broom. 

Infusum  Scoparii  (B.  P.),  1-2  fl.  oz. 

Succus  Scoparii  (B.  P.),  1-2  fl.  drs. 

^Sparteinse  Sulphas  (U.  S.  P.)  (C15H26N2H2SO,  +  4H2O),  colorless,  white 
crystals  with  a  saline  bitter  taste,  very  soluble  in  water  and  alcohol.  The 
dose  recommended  by  different  clinicians  as  of  benefit  in  heart  disease  varies 
from  0.004-0.8  G.  (TV-12  grs.)  in  the  course  of  24  hours.  It  may  be  given  in 
doses  of  0.1  G.  (2  grs.)  with  perfect  safety. 

Uses.  —  Broom  tops  are  used  as  a  feeble  diuretic,  generally  in  the 
form  of  a  decoction  (16  G.  in  250  c.c.  of  water,  or  J  oz.  in  a  half  pint 
in  divided  doses  in  24  hours),  or  infusion  (B.  P.).  Sparteine  has  been 
advised  in  heart  disease,  but  is  of  no  value  here.  It  has  also  been 
proposed  to  paralyze  the  terminations  of  the  vagus  with  it  before 
the  administration  of  chloroform,  the  object  being  to  avoid  the  reflex 
syncope,  but  a  small  dose  of  atropine  would  be  preferable.  It  has  also 
been  suggested  as  a  local  anaesthetic  in  ophthalmology,  but  has  only  a 
feeble  action. 

BIBLIOGRAPHY. 

Pick.     Arch.  f.  exp.  Path.  u.  Pharm.,  i.,  p.  397. 

Masius.     Bull,  de  1'Acad.  Koy.  de  Med.  de  Beige,  1887. 

Oushny  and  Matthews.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv.,  p.  129. 

Muto  and  Ishizaka.     Ibid.,  1.,  p.  1. 


266  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


XI.     NICOTINE  AND  LOBELINE. 

Nicotine,  the  well-known  alkaloid  of  tobacco  (Nicotiana  tabacum),  is 
a  volatile  fluid,  possessing  a  strong  alkaline  reaction,  and  forming  salts 
with  acids,  most  of  which  are  amorphous.  It  is  a  combination  of 
pyridine  with  a  hydrated  pyrrol  ring  as  shown  by  the  structural 
formula — 


Nicotine  is  the  only  constituent  of  tobacco  which  possesses  any 
toxicological  interest,  although  several  other  alkaloids  are  present  in 
comparatively  small  amounts.  It  is  accompanied  by  a  volatile  oil  in 
dried  tobacco,  but  this  is  only  developed  during  the  processes  of  pre- 
paration and  seems  to  have  no  action  apart  from  that  of  the  other  vola- 
tile oils.  The  odor  and  flavor,  and  probably  the  "  strength,"  of  to- 
bacco depends  in  part  upon  the  quantity  and  quality  of  this  oil,  in  part 
on  some  products  of  the  decomposition  of  nicotine.  Absolutely  pure 
nicotine  has  comparatively  little  odor,  but  it  decomposes  when  kept, 
becomes  dark  colored  and  acquires  the  characteristic  odor  of  tobacco. 

Another  alkaloid  which  is  practically  identical  with  nicotine  in  its 
pharmacological  action  is  Piturine  (C12H16N2),  which  is  derived  from 
the  pituri  plant  (Duboisia  Hopwoodii).  The  leaves  of  the  pituri  are 
said  to  be  used  by  the  Australian  natives  in  the  same  way  as  tobacco 
by  the  civilized  races. 

Lobeline  (C18H23NO2),  an  alkaloid  obtained  from  Lobelia  inflata  or 
Indian  Tobacco,  resembles  nicotine  very  closely  in  its  action,  and  may 
be  discussed  along  with  it. 

Tobacco  is  not  used  in  therapeutics,  but  is  of  great  hygienic  im- 
portance, and  nicotine  possesses  considerable  biological  interest  from 
the  results  obtained  by  Langley  by  its  use  in  physiology  in  recent  years. 
Lobelia  has  a  somewhat  restricted  field  of  usefulness  in  therapeutics, 
in  which  it  is  prescribed  in  asthma.  These  alkaloids  act  chiefly  on  the 
central  nervous  system,  the  sympathetic  ganglia,  and  the  terminations 
of  the  motor  nerves. 

Symptoms. — Poisonous  doses  administered  to  man  or  other  mam- 
mals cause  a  hot,  burning  sensation  in  the  mouth,  which  spreads  down 
the  oesophagus  to  the  stomach,  and  is  followed  by  salivation,  nausea, 
vomiting  and  sometimes  purging.  The  breathing  is  quick,  deep  and 
labored,  and  is  often  accompanied  by  moist  rales.  The  pulse  is  gen- 
erally slow  and  somewhat  weak  at  first  and  then  becomes  very  rapid, 
but  after  very  large  doses  may  be  first  accelerated  and  then  slow  and 


NICOTINE  AND  LOBELINE. 


267 


feeble.  Some  mental  confusion,  great  muscular  weakness,  giddiness  and 
restlessness  are  followed  by  loss  of  coordinating  power  and  partial  or 
complete  unconsciousness. 

Clonic   convulsions    set    in  FIG.  24. 

later,  accompanied  by  fibril- 
lary  twitching  of  various 
muscles,  and  eventually  a 
tetanic  spasm  closes  the 
scene  by  arresting  the  res- 
piration. In  other  instances 
the  convulsions  are  followed 
by  complete  relaxation  of 
all  parts  of  the  body,  the 
reflexes  disappear,  the  res- 
piration becomes  slow  and 
weak  and  finally  ceases,  the 
heart  continuing  to  beat 
for  some  time  afterwards. 
Very  large  doses  of  nico- 
tine may  prove  fatal  within 
a  few  seconds ;  the  symp- 
toms are  those  of  sudden 
paralysis  of  the  central 
nervous  system  including 
the  respiratory  centre,  and 
no  convulsions  are  de- 
veloped. 

In  the  frog  the  same  ex- 
citement and  violent  convul- 
sions are  seen  as  in  mam- 
mals, but  the  respiration 

SOOn    Ceases,  and    there     fol-  Diagram  of  the  regulating  nerves  of  the  heart.     P,  inhib- 

,                                   ,         .     ,,  itory  fibres  arising  in  the  vagus  centre  in  the  medulla  ob- 

lOWS     a         Cataleptic        Stage  longata  and  terminating  around  ganglion  cells  in  the  auricle 

i  .    i     .  i            .         -,  (A).     The  axis  cylinders  issuing  from  these  cells  terminate 

in  Which  tile  animal  assumes  on  the  muscular  "fibres  of  the  auricle  and  ventricle  (  V).    R, 

offifn/l«  accelerator  fibres  issuing  from  the  spinal  cord  and  termi- 

attitude.  nating  around  ganglion  cells  in  the  stellate  ganglion  G.    The 

lorrc  QTVI  nrr»ccorl   in  axis  fibres  of  these  ganglion  cells  run  through  the  Annulus 

1  Vieussenii  and  terminate  on  the  muscular  fibres  of  the  auri- 

front    Of    the     Sternum,    and  cle  and  ventricle.     N,  y  points  at  which  nicotine,  coniine, 

.                              .  curanne,  etc.,  act — the  ganglion  cells  surrounded  by  the 

are    rigid,    the    thighs  are  at  terminations  of  the  nerves.     M,  points  at  which  muscarine 

.    -.                ,                   ,             .         n  and  atropine  act — the  terminations  of  the  fibres  which  arise 

right    angles    to    the  aXIS  OI  from  the  intra-cardiac  ganglia. 

the  body  and  the  legs  are 

flexed  on  them  but  are  not  rigid.  When  a  leg  is  drawn  down  it  at 
once  returns  to  its  original  position,  and  the  frog  still  attempts  to 
escape  when  it  is  aroused.  Fibrillary  contractions  are  observed  in 
many  of  the  muscles.  Somewhat  later,  the  reflexes  disappear,  the 
muscles  become  flaccid,  and  eventually  complete  paralysis  occurs  from 
a  curara-like  action  on  the  terminations  of  the  nerves. 

Nicotine  has  but  little  toxic  action  on  the  lowest  invertebrates,  but 
as  the  nervous  system  begins  to  be  differentiated  it  causes  paralysis, 


268  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION^. 

and  still  higher  in  the  scale  the  paralytic  action  is  preceded  by  a  stage 
of  stimulation. 

Circulation.  —  The  action  on  the  circulation  is  extremely  complex, 
as  a  number  of  factors  are  involved.  After  moderate  quantities  the 
heart  is  slow  and  may  stand  still  in  diastole  for  a  few  seconds,  but  then 
recovers  gradually  and  regains  its  former  rhythm  or  becomes  somewhat 
quicker.  The  slow  pulse  is  due  to  stimulation  of  the  ganglia  on  the 
vagus  nerve  (Fig.  24,  N),  exactly  the  same  effects  being  produced  as 
by  stimulation  of  the  vagus  fibres  in  the  neck.  It  is  not  affected  by 
section  of  the  cervical  pneumogastric,  as  the  path  from  the  ganglia  to 
the  cardiac  muscle  fibres  is  still  intact,  but  on  the  other  hand,  it  is  pre- 
vented by  atropine,  which  acts  on  the  extreme  terminations  of  the  in- 
hibitory fibres,  and  therefore  blocks  the  passages  of  impulses  from  the 
ganglia  to  the  muscle.  It  is  also  prevented  by  a  number  of  drugs,  such 
as  curara  and  coniine,  which  paralyze  the  ganglia. 

This  stimulation  of  the  ganglia  is  of  but  short  duration,  soon  passing 
into  paralysis,  which  obstructs  the  passage  of  the  inhibitory  impulses 
from  above.  On  stimulating  the  vagus  after  nicotine  there  is  conse- 
quently no  slowing  of  the  heart  but  often  some  acceleration,  due  to  the 
fact  that  the  accelerating  fibres  running  along  with  the  inhibitory  in 
the  vagus  nerve  have  no  ganglionic  apparatus  in  the  heart,  and  are 
therefore  unaffected  by  nicotine.  Although  inhibitory  impulses  can 
no  longer  reach  the  heart  from  above,  the  intracardiac  inhibitory 
neuron  is  still  intact,  and  stimulation  of  the  venous  sinus  in  the  frog 
still  causes  arrest  of  the  heart  exactly  as  in  the  normal  animal.  The 
stimulating  current  here  reaches  the  inhibitory  nerves  beyond  the 
paralyzed  ganglia  (Fig.  24,  X\  and  these  preserve  their  usual  irrita- 
bility. In  the  same  way  a  number  of  poisons  which  act  upon 
the  extreme  terminations  of  the  inhibitory  fibres  in  the  heart  muscle 
(Fig.  24,  M )  can  slow  the  rhythm  even  after  the  ganglia  have  been 
paralyzed  by  nicotine  (see  the  Pilocarpine  and  Muscarine  group).  The 
results  of  the  stimulation  and  subsequent  paralysis  of  the  ganglionic 
structures  on  the  inhibitory  fibres  by  nicotine  are  the  preliminary  slow- 
ing and  subsequent  slight  acceleration  of  the  heart  rhythm  seen  in  both 
cold-  and  warm-blooded  animals.  In  larger  doses  nicotine  produces 
no  slowing  of  the  heart,  owing  to  the  ganglia  being  paralyzed  imme- 
diately, without  previous  stimulation. 

In  addition  to  its  action  on  the  peripheral  inhibitory  ganglia,  nico- 
tine seems  to  stimulate  the  vagus  centre  in  the  medulla,  as  the  slow- 
ing is  greater  when  the  vagi  are  intact  than  when  they  are  divided. 
But  apart  from  this  action  on  the  inhibitory  apparatus,  nicotine  pos- 
sesses some  direct  action  on  the  heart  muscle,  which  appears  to  be  first 
stimulated  and  then  depressed.  Accordingly,  when  the  inhibitory  appa- 
ratus has  been  previously  paralyzed,  moderate  quantities  increase  the 
rate  of  the  heart  beat  considerably,  while  very  large  ones  slow  and 
weaken  it.  It  has  been  supposed  that  this  quickening  is  due  to  action 
on  the  accelerator  centre,  or  on  the  ganglia  on  the  course  of  the  sym- 
pathetic accelerator  fibres  (N',  Fig.  24),  but  this  seems  not  to  be  the 


NICOTINE  AND  LOBELINE.  269 

only  cause,  for  Wertheimer  found  the  acceleration  continue  even  after 
extirpation  of  these  ganglia.  The  quickening  must  be  attributed 
in  part,  or  wholly  to  action  on  the  cardiac  muscle,  or  on  the  termina- 
tions of  the  accelerator  nerves  in  it.  The  subsequent  slowing  and  weak- 
ness is  undoubtedly  due  to  a  paralyzing  action  on  the  muscle  itself. 

On  the  injection  of  nicotine  into  a  vein  or  subcutaneously  an  im- 
mense augmentation  of  the  arterial  tension  occurs ;  this  may  be  due 
in  part  to  stimulation  of  the  vaso-constrictor  centre  in  the  medulla,  but 
is  to  be  ascribed  chiefly  to  peripheral  influences,  for  it  has  been  ob- 
served after  section  and  even  after  total  removal  of  the  spinal  cord. 
The  vaso-constrictor  nerves  pass  through  ganglia  on  their  way  to  the 
vessels  and  the  rise  of  the  blood-pressure  seems  to  be  mainly  caused 
by  a  stimulation  of  these  ganglia. 

The  constriction  of  the  vessels  can  be  observed  in  many  parts  of  the  body 
— mesentery,  foot,  rabbit's  ear,  etc.  In  these  parts  the  pallor  produced  by 
the  narrowing  of  the  vessels  is  followed  by  redness  and  congestion  owing  to 
the  paralysis  of  the  ganglia,  and  at  the  same  time  the  pressure  falls  to  a 
level  somewhat  below  the  normal.  In  some  parts  of  the  body  no  constric- 
tion of  the  vessels  occurs  ;  for  example,  the  dog's  lip  and  mouth  are  con- 
gested first  and  then  become  pale.  This  flushing  seems  partly  due  to  the 
stimulation  of  the  ganglionic  apparatus  on  the  vaso-dilator  fibres  for  these 
parts,  but  cannot  be  wholly  explained  thus,  for  it  occurs  also  after  removal 
of  the  superior  cervical  ganglion,  although  to  a  less  marked  degree.  It  may 
therefore  be  caused  in  part  by  direct  action  on  the  vessels. 

After  a  few  minutes  the  blood-pressure  falls  to  the  normal  level  or 
lower,  but  a  second  injection  again  produces  a  similar  rise  in  the  arterial 
tension,  unless  the  first  was  large  enough  to  paralyze  the  ganglia. 
Eventually  nicotine  lowers  the  blood-pressure  owing  to  the  weakening 
action  on  the  heart. 

Respiration.  —  The  respiration  is  at  first  rapid  and  shallow  with  some 
deficiency  in  the  expiratory  movements,  but  after  a  time,  while  main- 
taining the  acceleration,  it  becomes  deeper.  It  is  liable  to  be  interrupted 
at  this  stage  by  the  convulsions,  but  if  these  do  not  prove  fatal,  it 
gradually  becomes  slower  while  remaining  deep.  Later,  pauses  in  the 
position  of  expiration  appear,  and  the  movements  become  weaker  until 
they  disappear,  the  animal  dying  of  asphyxia.  The  rapid,  shallow 
movements  in  the  beginning  of  the  intoxication  are  absent  in  animals 
in  which  the  pneumogastric  nerves  have  been  previously  divided,  so 
that  this  phenomenon  appears  to  be  due  to  the  alkaloid  acting  as  an 
irritant  to  the  pulmonary  branches  of  the  pneumogastric.  The  later 
features  are  caused  by  its  acting  on  the  respiratory  centre  directly,  first 
stimulating  and  then  paralyzing  it.  After  large  doses  this  direct  action 
alone  may  be  elicited.  The  paralysis  of  the  respiration  is  the  cause 
of  death,  the  heart  continuing  to  beat  for  some  time  afterwards  al- 
though slowly  and  weakly. 

The  bronchial  muscle  relaxes  after  a  transient  constriction  when 
nicotine  or  lobeline  is  ingested,  these  changes  being  brought  about  by 
stimulation  and  subsequent  depression  of  the  ganglia  on  the  course  of  the 
innervating  fibres.  The  dilatation  of  the  bronchi  is  more  marked  when 
they  have  been  previously  in  a  state  of  constriction  (Dixon  and  Brodie). 


270 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


FIG.  25. 


Most  of  the  Secretions  are  increased  temporarily  by  nicotine.  The 
glands  investigated  have  generally  been  the  salivary,  where  it  is  found 
that  the  secretion  is  increased  by  the  injection  of  small  quantities,  but 

is  afterwards  depressed,  while  large 
doses  diminish  it  at  once.  The  seat 
of  action  is  again  the  ganglionic  ap- 
paratus on  the  secretory  nerves.  If 
the  chorda  tympani  be  stimulated  in 
the  normal  animal  a  large  secretion 
of  saliva  at  one  follows,  but  if  a 
sufficient  quantity  of  nicotine  be  in- 
jected no  such  effect  follows  its 
stimulation.  '  If,  however,  the  nerve 
fibres  be  stimulated  between  the 
ganglion  cells  and  the  gland  (at 
X  in  Fig.  25),  the  secretion  again  fol- 
lows as  before.  On  the  other  hand, 
nicotine  increases  the  secretion  whether 
the  chorda  be  intact  or  not,  but  ceases 
to  act  if  the  connection  between  the 
ganglion  cells  and  the  gland  be  inter- 
rupted. These  results  can  only  be  in- 
terpreted by  nicotine  first  stimulating 
and  then  paralyzing  the  ganglia  on  the 
course  of  the  chorda  tympani.  In  the 
same  way  it  first  stimulates  and  then 
paralyzes  the  ganglia  which  lie  in  the 
course  of  the  sympathetic  salivary 
fibres.  Pilocarpine  and  muscarine 
cause  profuse  salivation  after  nicotine, 
because  they  stimulate  the  terminations 
of  the  nerves  in  the  gland  cells,  and  it 
is  therefore  immaterial  whether  the 
connection  with  the  central  nervous 
system  be  interrupted  or  not.  On  the 
other  hand,  the  reflex  secretion  of  saliva 
normally  produced  by  irritation  of  the 
mouth  or  by  chewing  is  prevented  by 
nicotine.  Atropine  stops  the  secretion 
produced  by  nicotine  by  paralyzing  the 
extreme  terminations  of  the  nerves. 

The  other  secretory  glands  are  affec- 
ted in  the  same  way  by  nicotine,  and 
although  the  details  have  not  been 
worked  out  so  carefully  as  for  the  sali- 
vary glands,  there  is  no  question  that  their  secretions  are  first  in- 
creased by  the  stimulation  of  the  ganglia  on  the  course  of  their 
secretory  nerves,  and  then  lessened  by  their  paralysis.  Thus  the 


Diagram  of  theinnervation  cf  the  sub- 
maxillary  gland.  P,  a  fibre  of  the  chorda 
tympani  issuing  from  the  pons  Varplii 
and  after  "a  devious  course  terminating 
around  a  ganglion  cell  in  the  hilus  of  the 
submaxillary  gland.  The  axis  from  this 
ganglion  cell  runs  to  the  secretory  epi- 
thelium. 7?,  a  fibre  issuing  from  the  spinal 
cord  and  after  running  through  the  sym- 
pathetic chain  in  the  neck,  terminating 
around  a  ganglion  cell  in  the  superior  cer- 
vical ganglion  G.  The  axis  from  this  cell 
runs  to  the  secretory  epithelium.  In  the 
diagram  the  nerves  are  represented  as 
running  to  separate  acini.  N,  N',  gang- 
lion cells  surrounded  by  the  termina- 
tions of  the  nerves — the  points  at  which 
nicotine  acts.  M,  the  terminations  of  the 
secretory  fibres  connected  with  the  chorda 
tympani — the  points  at  which  atropine, 
muscarine,  and  pilocarpine  act. 


NICOTINE  AND  LOBELINE.  271 

sweat  secretion  is  found  to  be  markedly  increased,  as  also  the 
secretion  of  the  bronchial  mucous  glands.  The  urine  and  bile  have 
not  been  shown  to  be  affected  by  nicotine,  and  as  their  secretion  does 
not  seem  to  be  so  dependent  upon  nervous  influences,  it  is  probable 
that  it  is  but  little  changed  in  amount. 

Nicotine  produces  extreme  Nausea  and  Vomiting  when  taken  even 
in  comparatively  small  quantities,  a  fact  which  is  generally  recognized 
by  tyros  in  smoking.  This  may  be  in  part  central  in  origin,  but  is 
mainly  due  to  the  powerful  contractions  of  the  stomach  walls.  This 
contraction  extends  throughout  the  intestinal  tract,  so  that  repeated 
Evacuation  of  the  Bowel  occurs. 

Somewhat  larger  quantities  may  lead  to  a  tetanic  contraction  of  the 
whole  intestine  with  almost  complete  obliteration  of  the  lumen.  This 
exaggeration  of  the  peristaltic  contraction  is  probably  due  to  stimula- 
tion of  the  motor  nervous  apparatus  in  the  intestinal  wall,  and  a  subse- 
quent paralysis  of  these  structures  leads  to  a  failure  of  local  stimuli  to 
induce  peristalsis.  A  further  effect  of  nicotine  in  the  bowel  is  due  to 
its  stimulating  the  ganglia  on  the  fibres  of  the  splanchnic  which 
inhibit  the  rhythmical  pendulum  movements.  These  are  arrested  by 
the  injection  of  nicotine,  but  return  in  exaggerated  form  as  the  gan- 
glionic  stimulation  passes  into  paralysis.  The  mesenteric  vessels  are 
narrowed  at  first  from  stimulation  of  the  ganglia  on  the  course  of  the 
vaso-constrictor  nerves,  but  congestion  follows  the  depression  of  these 
ganglia  and  the  consequent  fall  in  blood-pressure. 

Similar  changes  are  produced  by  nicotine  in  the  bladder  and  uterus, 
both  of  which  are  thrown  into  tetanic  contraction.  The  urine  is  there- 
fore expelled  very  soon  after  the  injection  of  nicotine,  and  this  probably 
gave  rise  to  the  erroneous  view  that  the  renal  secretion  was  increased. 

The  action  of  nicotine  on  the  Pupil  varies  in  different  animals,  for 
while  in  the  cat  and  dog  its  application  either  intravenously  or  locally 
produces  marked  but  transitory  dilation,  in  the  rabbit  partial  con- 
striction sets  in  immediately.  In  cases  of  acute  poisoning  in  man  con- 
traction is  generally  seen  at  first  and  is  followed  by  dilatation.  In 
birds  nicotine  causes  very  marked  contraction  of  the  pupil,  apparently 
owing  to  direct  action  on  the  muscles  of  the  iris.  The  size  of  the  pupil 
is  regulated  by  two  sets  of  nerves,  the  motor  oculi  and  the  sympathetic, 
and  the  ciliary  fibres  of  both  of  these  are  interrupted  by  ganglia  in 
their  passage  from  the  brain  to  the  iris,  those  of  the  motor  oculi  by  the 
ciliary  ganglion,  those  of  the  sympathetic  by  the  superior  cervical 
ganglion  (see  Fig.  26,  p.  287) ;  the  varying  effects  of  nicotine  may 
be  due  to  its  stimulating  the  one  ganglion  more  strongly  in  one  species 
of  animals,  the  other  in  another.  It  is  found,  however,  that  atro- 
pine  does  not  remove  the  effects  of  nicotine  on  the  rabbit's  eye,  which 
would  seem  to  indicate  an  action  on  the  muscular  fibres  of  the  iris. 
Several  other  effects  on  the  orbital  muscles  are  seen  ;  thus  in  cats 
and  dogs  the  nictitating  membrane  is  withdrawn,  the  eye  opens  and  is 
directed  forwards,  while  in  the  rabbit  these  symptoms  are  preceded  by 
a  stage  in  which  the  nictitating  membrane  is  spread  over  the  cornea 


272  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

and  the  eye  is  tightly  closed.  These  are  probably  produced  by  action 
on  the  superior  cervical  ganglion. 

Nicotine,  then,  first  stimulates  and  later  paralyzes  all  the  Sympa- 
thetic Ganglia,  whether  applied  locally  to  them  or  injected  into  the  cir- 
culation. In  these  ganglia,  the  characteristic  formation  is  the  basket- 
like  arrangement  of  the  terminations  of  the  entering  nerve,  which 
surround  a  large  nerve  cell  from  which  an  axis  cylinder  runs  to  the 
muscle  or  secretory  cell.  A  nerve  impulse  from  the  central  nervous 
system  passes  from  the  basket  to  the  cell  and  thence  to  the  periphery. 
Langley  has  recently  shown  that  small  quantities  of  nicotine  stimulate 
the  cell  of  the  peripheral  neuron,  for  the  same  effect  is  obtained  from 
the  application  of  the  poison  to  the  ganglion  whether  the  basket-like 
terminations  round  the  cell  are  normal  or  have  degenerated.  This 
renders  it  probable  that  the  paralysis  of  the  ganglia  observed  from 
larger  quantities  of  nicotine  is  also  due  to  action  on  the  cell  and  not  on 
the  terminations. 

In  the  frog  nicotine  produces  fibrillary  contraction  of  the  muscles, 
which  is  not  prevented  by  previous  division  of  the  nerves  leading  to 
them,  but  disappears  on  the  injection  of  curara ;  on  the  other  hand,  the 
paralysis  of  the  motor  terminations  by  curara  may  be  partially  removed 
by  small  quantities  of  nicotine.  This  indicates  that  the  fibrillary  con- 
tractions arise  neither  from  action  on  the  central  nervous  system  nor 
on  the  muscle  itself,  but  from  stimulation  of  the  terminations  of 
the  motor  nerves.  These  terminations  are  subsequently  paralyzed  if 
the  quantity  injected  be  large  enough.  In  mammals  the  twitching  of 
the  muscles  is  prevented  by  section  of  the  nerves,  and  is,  therefore,  due 
to  central  action,  but  large  quantities  of  nicotine  cause  paralysis  of  the 
nerve  ends  exactly  like  curara.  The  nerves  of  the  orbital  muscles  are 
found  to  be  paralyzed  sooner  than  those  of  the  rest  of  the  body. 

Nicotine  does  not  seem  to  act  on  Muscular  Tissue  in  general, 
although  some  obscure  symptoms  have  been  ascribed  to  changes  in  the 
cardiac  and  iris  muscle. 

The  convulsions  seen  in  both  cold-  and  warm-blooded  animals  evi- 
dence the  influence  of  nicotine  on  the  Central  Nervous  System.  The 
spinal  cord  is  thrown  into  a  condition  of  exaggerated  irritability,  and 
the  reflexes  are  correspondingly  increased,  but  the  convulsions  do  not 
seem  to  be  due  so  much  to  the  spinal  cord  as  to  the  medulla  oblongata 
and  hind  brain,  for  they  are  not  tonic  but  clonic  in  character,  and  are 
much  weaker  after  division  of  the  cord  immediately  below  the  medulla 
than  in  the  intact  animal.  The  medullary  stimulation  also  betrays 
itself  in  the  rapid  and  deep  respiration,  and  is  perhaps  in  part  respon- 
sible for  the  inhibitory  slowing  of  the  heart  and  the  rise  in  the  blood- 
pressure.  The  higher  centres  in  the  brain  seem  to  participate  but 
little  in  the  stimulant  action  of  nicotine,  which  is  short-lived,  and 
soon  gives  way  to  marked  depression  of  the  whole  central  nervous 
system,  manifested  in  the  slow  respiration,  the  low  blood-pressure,  the 
disappearance  of  the  reflex  movements  and  the  final  unconsciousness. 

The  Excretion  of  nicotine  is  probably  carried  on   mainly  by  the 


NICOTINE  AND  LOBELINE.  273 

kidneys,  for  it  is  found  in  the  urine  very  soon  after  it  enters  the  blood. 
It  has  also  been  detected  in  the  saliva  and  perspiration.  It  has  been 
shown  repeatedly  that  nicotine  and  some  other  alkaloids  are  weakened 
in  toxic  effect  or  rendered  entirely  inactive  by  being  mixed  with  an 
extract  of  the  liver  or  of  the  suprarenal  capsules ;  but  no  satisfactory 
explanation  is  forthcoming,  though  there  is  every  reason  to  suppose 
that  much  of  the  nicotine  absorbed  from  the  stomach  and  intestine  is 
thus  modified  in  its  passage  through  the  liver. 

When  small  quantities  of  nicotine  are  ingested  repeatedly,  the  body 
soon  gains  a  certain  Tolerance,  and  no  symptoms  whatever  are  pro- 
duced by  doses  which  would  in  ordinary  cases  produce  grave  poison- 
ing. A  familiar  example  of  this  tolerance  is  seen  in  the  practice  of 
smoking.  The  first  use  of  tobacco  is  in  the  great  majority  of  indi- 
viduals followed  by  vomiting  and  depression  which  may  even  amount 
to  collapse,  but  after  a  few  experiences  no  symptoms  follow  smoking, 
owing  to  the  cells  of  the  body  becoming  tolerant  of  the  poison.  In 
some  individuals  no  such  tolerance  is  developed,  and  in  every  case  the 
tolerance  is  much  more  limited  and  more  difficult  to  acquire  than  that 
for  morphine.  In  animal  experiments  it  is  often  found  that  while 
one  application  of  nicotine  produces  considerable  ganglionic  stimula- 
tion, the  second  has  much  less  effect.  This  is  probably  due  not  to  the 
establishment  of  tolerance,  but  to  the  first  dose  having  produced 
primary  stimulation  and  then  depression  of  the  ganglia,  this  depression, 
while  not  amounting  to  complete  paralysis,  being  sufficient  to  counter- 
act to  some  extent  the  stimulant  action  of  the  second  injection. 

Nicotine  and  Piturine  are  not  used  in  therapeutics.  Tobacco  was 
formerly  employed  in  the  reduction  of  intestinal  hernia,  and  for  this 
purpose  was  injected  into  the  rectum  in  the  form  of  an  infusion.  Sev- 
eral cases  of  poisoning  and  the  introduction  of  general  anaesthesia  led 
to  its  disuse. 


Tobacco. 

Tobacco  had  been  in  use  among  the  aboriginal  tribes  of  America 
before  they  became  known  to  civilization.  It  was  introduced  into 
Europe  soon  after  the  discovery  of  America,  and  its  use  as  an  article 
of  luxury,  beginning  in  England,  soon  spread  to  the  continent,  and  in 
spite  of  papal  bulls  and  numerous  efforts  on  the  part  of  the  secular 
authorities,  has  continued  to  enthral  a  considerable  portion  of  the 
human  race.  The  most  widespread  use  of  tobacco  —  smoking — is  also 
the  most  ancient  one,  having  been  that  of  the  aboriginal  Indians. 
Snuff-taking,  introduced  by  Francis  II.  of  France,  remained  fashion- 
able for  a  long  time,  but  is  now  almost  obsolete.  Tobacco-chewing 
is  a  more  modern  development,  but  shows  no  signs  of  abatement. 
Curiously  enough,  the  leaves  of  the  pituri  plant,  which,  as  has  been 
mentioned,  contain  an  alkaloid  nearly  allied  to  nicotine,  are  formed 
into  a  mass  and  chewed  by  the  natives  of  Australia.  In  smoking, 
snuffing  or  chewing,  nicotine  is  absorbed.  It  has  been  stated  and  the 
18 


274  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

statement  has  received  an  undeservedly  wide  circulation,  that  tobacco 
smoke  contains  no  nicotine  but  merely  the  products  of  its  decomposi- 
tion ;  but  as  a  matter  of  fact,  tobacco  smoke,  whether  from  cigars  or 
pipes,  contains  a  certain  amount  of  the  alkaloid  itself,  along  with  pyri- 
dine  and  many  of  its  compounds.  The  amount  of  nicotine  in  tobacco 
smoke  cannot  be  definitely  stated,  as  it  depends  on  the  kind  of  tobacco, 
as  well  as  on  the  way  in  which  it  is  inhaled  ;  but  only  a  small  propor- 
tion of  that  contained  in  tobacco  passes  over  in  the  smoke.  In  snuff 
the  nicotine  is  generally  small  in  amount,  while  in  chewing  tobacco 
there  is  generally  a  varying  amount  of  foreign  matter,  such  as  molasses. 
The  enjoyment  derived  from  the  use  of  tobacco  has  never  been  ex- 
plained, and  it  is  not  even  proved  that  nicotine  is  essential  to  the 
pleasurable  results ;  consideration  of  the  pharmacological  effects  of 
nicotine  gives  no  clue,  for  these  are  of  the  opposite  nature.  It  has 
been  suggested  that  smoking  gives  repose  and  thereby  improves  intel- 
lectual work,  but  this  is  denied  'by  many  habitual  smokers.  It  has 
also  been  stated  and  denied  that  the  mental  energy  is  reduced  by  the 
use  of  tobacco,  and  an  attempt  has  been  made  to  demonstrate  this  by 
measuring  the  amount  of  work  done  with  and  without  tobacco ;  but 
investigators  are  not  agreed  on  the  results,  which  probably  depend 
largely  upon  the  individual.  One  fact  is  certain,  that  the  tobacco  habit 
cannot  be  compared  with  the  use  of  such  drugs  as  morphine,  cocaine, 
or  alcohol,  for  it  is  not  taken  with  the  purpose  of  producing  stimulation 
or  depression  of  the  central  nervous  system,  and  it  seems  doubtful 
whether  the  nicotine  ordinarily  absorbed  really  has  any  action  whatso- 
ever. Perhaps  the  local  effects  on  the  mouth,  nose  and  throat  play  a 
larger  part  in  the  effects  of  tobacco  than  is  generally  recognized.  A 
certain  amount  of  rhythmic  movement  demanding  no  exertion  seems 
in  itself  to  have  a  soothing,  pleasure-giving  effect,  for  it  is  otherwise 
impossible  to  explain  the  satisfaction  enjoyed  by  many  in  chewing 
tasteless  objects,  such  as  gum  or  straws.  A  curious  fact  which  tends 
to  show  that  tobacco  smoking  is  not  carried  on  for  the  sake  of  the 
nicotine  absorbed  is  that  the  pleasure  derived  from  a  pipe  or  cigar  is 
abolished  for  many  persons  if  the  smoke  is  not  seen,  as  when  it  is 
smoked  in  the  dark. 

Most  people  may  indulge  in  the  moderate  use  of  tobacco  for  many 
years  with  perfect  impunity,  but  its  excessive  use  is  followed  in  many 
individuals  by  a  number  of  symptoms,  some  of  them  trivial,  others 
indicating  grave  changes  in  important  organs. 

One  of  the  commonest  effects  of  overindulgence  in  tobacco  is  a  chronic 
inflammation  of  the  throat  and  upper  parts  of  the  respiratory  passages, 
leading  to  hoarseness  and  excessive  secretion  of  the  mucous  glands. 
This  is  explained  by  the  constant  application  to  the  throat  of  an  irri- 
tant, alkaline  vapor,  and  is  probably  not  due  to  the  specific  action  of 
nicotine.  A  similar  irritated  condition  of  the  tongue  is  frequently  met 
with,  more  especially  when  the  hot  vapor  is  directed  especially  on  one 
part,  as  in  pipe  smoking,  and  it  is  sometimes  stated  that  the  constant 
irritation  thus  produced  renders  the  tongue  and  lip  more  liable  to  can- 


NICOTINE  AND  LOBELINE.  275 

cerous  disease.  -Dyspepsia,  want  of  appetite,  and  consequent  loss  of 
flesh  may  also  be  explained  by  the  local  irritation  produced  by  the 
nicotine  swallowed  in  the  saliva.  A  common  result  of  the  abuse  of 
tobacco  is  palpitation  and  irregularity  of  the  heart,  which  has  been 
attributed  to  changes  in  the  inhibitory  mechanism.  Another  import- 
ant symptom  is  dimness  of  vision,  especially  for  colors,  and  imperfect 
accommodation,  which  may  go  on  to  complete  blindness  in  one  or  both 
eyes.  In  early  cases  the  retina  often  appears  pale,  and  if  the  condition 
persists,  atrophy  of  the  optic  nerve  may  result,  probably  following  on 
degenerative  changes  in  the  ganglion  cells  of  the  macular  region  of  the 
retina.  The  hearing  is  said  to  be  affected  by  excessive  smoking,  but 
the  symptoms  are  indistinct  and  variable.  Nervous  symptoms  such  as 
tremor,  exaggeration  of  the  reflexes,  headache  and  giddiness  are  some- 
times developed  in  workmen  in  tobacco  factories,  but  they  do  not  seem 
to  be  induced  by  smoking  or  chewing  tobacco,  though  depression,  muscu- 
lar weakness  and  giddiness  are  sometimes  complained  of.  In  the  great 
majority  of  cases  of  chronic  tobacco  poisoning,  the  symptoms  disappear 
on  abandoning  the  habit,  or  even  on  restricting  the  daily  consump- 
tion. A  series  of  subjective  and  even  objective  symptoms  are  said  to 
be  induced  in  neurotic  subjects  by  the  sudden  withdrawal  of  tobacco. 
Esser  has  recently  stated  that  chronic  nicotine  poisoning  in  animals 
induced  marked  disturbance  of  the  heart,  and  that  degeneration  of  the 
vagus  fibres  are  recognizable  histologically ;  changes  have  also  been 
found  in  the  nerve  cells  of  the  spinal  cord  and  sympathetic  ganglia 
similar  to  those  described  under  chronic  alcoholic  poisoning. 

BIBLIOGRAPHY. 

Langley  and  Dickinson.  (Journ.  of  Phys.,  xi.,  p.  265),  give  all  the  more  important 
experimental  literature  up  to  1890. 

Langley,  Langley  and  Sherrington,  Langley  and  Anderson.  JOUIM.  of  Phys.,  xii.,  xiii., 
xv.,  and  xxvii.,  p.  224. 

Wertheimer  et  Colas.     Archiv  de  Physiol.  (5),  iii.,  1891,  p.  341. 

Bayliss  and  Starling.     Journ.  of  Phys.,  xxiv.,  p.  99. 

Hatcher.     Amer.  Journ.  of  Phys.,  xi.,  p.  17. 

Dixon  and  Brodie.     Journ.  of  Phys.,  xxix.,  p.  168. 

Esser.     Arch.  f.  exp.  Path.  u.  Pharm,  xlix.,  p.  190. 

Greenwood.     Journ.  of  Phys.,  xi.,  p.  573.     (Action  on  Li  vertebrates.) 

Moore  and  Row.     Journ.  of  Phys.,  xxii.,  p.  273. 

Winterberg.     Arch.  f.  exp.  Path.  u.  Phann.,  xliii.,  p.  400. 

Habermann.     Ztschr.  f.  physiol.  Chem.,  xxxiii.,  p.  55. 

Beyer.     Johns  Hopkins  Hospital  Reports,  ix.,  p.  111. 

Birch-Hirschfeld.     Arch.  f.  Ophthalmologie,  liii.,  p.  79. 

Lobeline. 

Lobeline  (C18H23NO2),  the  alkaloid  of  Lobelia  inflata  or  Indian 
Tobacco,  possesses  almost  exactly  the  same  action  as  nicotine  (Edmunds). 

PREPARATIONS. 

Lobelia  (U.  S.  P.,  B.  P.),  the  leaves  and  tops  of  Lobelia  inflata,  U.  S.  P.,  the 
dried  herb,  B.  P. 

Fluidextractum  Lobelia  (U.  S.  P.),  0.06-0.3  c.c.  (l-5mins.). 
Tinctura  Lobelia  (U.  S.  P.),  0.6-4  c.c.  (10-60  mins.). 
Tinctura  Lobelias  ^Etherea  (B.  P.),  5—15  mins. 


276  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Therapeutic  Uses. — Lobelia  was  formerly  used  as  an  emetic,  but  is  exceed- 
ingly depressant  and  unreliable,  and  if  vomiting  does  not  occur  is  liable  to  give 
rise  to  the  most  alarming  symptoms  of  poisoning.  The  only  condition  in  which 
it  is  now  used  at  all  is  spasmodic  asthma,  which  appears  to  arise  from  parox- 
ysmal contraction  of  the  bronchial  muscles.  Its  action  certainly  supports  this 
use  of  the  plant,  but  perhaps  it  aids  in  these  conditions  as  much  by  the  increased 
secretion  of  the  mucous  membranes  owing  to  the  nausea  as  through  its  action 
on  the  motor  nerves  of  the  bronchial  muscles.  Its  effects  must  be  carefully 
watched,  as  the  preparations  seem  to  vary  in  strength,  and  numerous  alarming 
symptoms  and  even  fatal  results  have  followed  its  use. 

BlBLIOGKAPHY. 

Oil.     Phil.  Med.  Times,  vi.,  p.  121,  1875. 
Ronnberg.     Inaug.  Diss.,  Kostock,  1880. 
Dreser.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi.,  p.  237. 
C.  W.  Edmunds.    Amer.  Journ.  of  Phys.,  xi.,  p.  79. 

XII.     THE  ATROPINE  SERIES. 

The  atropine  series  contains  a  number  of  very  closely  allied  alka- 
loids, of  which  the  chief  are  Atropine,  Hyoscyamine  and  Hyoscine  or 
Scopolamine.  They  are  found  in  several  plants  of  the  Solanacese  order, 
and  in  most  cases  several  of  them  occur  together. 

Atropine  may  be  broken  up  by  the  action  of  alkalies  into  an  alka- 
loid, Tropine,  and  Tropic  Acid.  The  former  is  a  pyridine  compound 
very  closely  allied  to  Ecgonine  (see  cocaine)  as  may  be  seen  by  its 
structural  formula,  while  the  latter  is  an  aromatic  acid. 

Atropine. 


Tropine  radicle.  Tropic  acid  radicle. 

CH2  — CH CHa 

N(CH3)CHO-CO  — CH  — C6H5 
CH2  — CH CH2  CH2OH 

Atropine  and  hyoscyamine  are  isomers,  and  in  fact  atropine  has 
recently  been  shown  to  be  racemic  hyoscyamine.  That  is,  atropine  is 
a  loose  combination  of  hyoscyamine  with  another  isomeric  body, 
dextro-hyoscyamine,  which  differs  from  the  ordinary  or  Isevo-hyoscy- 
amine  in  the  direction  in  which  it  rotates  a  ray  of  polarized  light. 
The  combination  of  these  two  hyoscyamines  to  form  atropine  exists 
only  in  the  solid  state ;  as  soon  as  atropine  is  dissolved  it  separates 
into  equal  quantities  of  dextro-  and  laevo-hyoscyamirie.  The  action 
of  atropine  is  thus  compounded  of  the  action  of  these  two  bodies, 
which  differ  very  greatly  in  their  pharmacological  effects,  although 
they  are  almost  identical  in  their  reactions  to  chemical  reagents.  Hyos- 
cyamine is  very  readily  changed  to  atropine,  and  this  generally  occurs 
to  a  large  extent  in  the  process  of  extraction  from  the  plants. 

Scopolamine  (hyoscine)  was  formerly  supposed  to  be  another  isomer 
of  atropine,  but  has  lately  been  shown  to  differ  slightly  in  its  formula, 
which  is  C17H21NO4.  It  is  very  closely  allied  to  atropine,  and  is 
decomposed  into  tropic  acid  and  Scopoline  (Oscine),  which  was  formerly 


ATROPINE  SERIES.  277 

supposed  to  be  isomeric  with  tropine,  but  has  been   shown  to  differ 
from  it  in  the  number  of  hydrogen  and  oxygen  atoms. 

A  number  of  other  alkaloids  have  been  described  in  different  plants,  generally 
associated  with  one  or  more  of  those  already  mentioned.  But  on  examination 
these  have  generally  proved  to  be  mixtures  of  atropine,  hyoscyamine  and  hyos- 
cine.  Thus  the  Duboisine  of  Duboisia  myoporoides,  the  Mandragorine  of  Man- 
dragora  (Mandrake)  and  the  Daturine  of  Datura  stramonium  have  all  failed  to 
maintain  their  position  as  new  bases  and  have  proved  to  be  mixtures  of  the 
established  alkaloids  in  varying  proportions.  Atropamine,  a  new  alkaloid  found 
by  Hesse  in  some  species  of  Belladonna,  diners  slightly  in  formula  from  atro- 
pine, from  which  it  may  be  formed  by  the  application  of  heat ;  it  is  decomposed 
into  a  substance  which  is  isomeric  with  tropine,  but  which  differs  from  it  in 
some  respects  and  which  has  been  called  fi-lropine.  Atropamine  is  isomeric  but 
not  identical  with  Belladonnine,  which  is  a  compound  of  yet  another  isomer  of 
tropine,  bellatropine.  Pseudo- hyoscyamine  is  said  to  differ  from  atropine  and 
hyoscyamine  in  some  of  its  chemical  relations,  but  has  not  been  the  subject  of 
much  work  as  yet.  Atroscine  is  isomeric  with  scopolamine,  and  the  same  rela- 
tion appears  to  exist  between  them  as  between  atropine  and  hyoscyamine. 

After  atropine  had  been  found  to  be  a  compound  of  tropine  and 
tropic  acid,  a  number  of  other  acids  were  attached  to  tropine  in  the 
same  way  as  tropic  acid.  These  artificial  alkaloids  are  known  as  Tro- 
peines,  and  in  action  resemble  atropine  in  some  points  while  differing 
from  it  in  others.  Further  study  of  the  action  of  these  tropeines  is 
exceedingly  desirable,  and  promises  to  be  of  considerable  value  in 
practical  therapeutics.  The  only  artificial  tropeine  which  has  as  yet 
been  used  in  medicine  is  the  compound  of  tropeine  and  oxytoluic  acid 
known  as  Homatropine.  Scopoleines  have  been  formed  by  substituting 
other  acids  for  the  tropic  acid  of  scopolamine,  but  none  of  them  has 
proved  of  value  in  therapeutics  as  yet. 

It  must  be  understood  that  the  combination  of  tropine  and  its  allies 
with  tropic  acid  does  not  partake  in  any  way  of  the  nature  of  the  com- 
bination of  an  ordinary  alkaloid,  such  as  morphine,  with  an  acid.  The 
bond  is  the  much  closer  one  seen  in  the  compound  ethers,  and  the 
resulting  substance  is  alkaline  and  combines  with  acids  to  form  salts 
exactly  as  other  alkaloids  do. 

The  chief  plants  containing  these  alkaloids  are  the  following : 
Atropa  Belladonna  (Deadly  nightshade),  containing  varying  quantities 
of  hyoscyamine  and  atropine,1  hyoscine,  and  sometimes  atropamine  and 
belladonnine. 

Hyoscyamus  niger  (Henbane),  containing  hyoscyamine  and  hyoscine, 
with  smaller  quantities  of  atropine. 

Datura  Stramonium  (Thornapple),  containing  atropine,  hyoscyamine, 
and  some  hyoscine. 

Of  less  importance  are : 

Duboisia  myoporoides,  containing  hyoscine  and  hyoscyamine,  together  with 
pseudo-hyoscyamine  and  other  alkaloids.  Another  species  of  Duboisia  contains 
piturine,  an  alkaloid  nearly  allied  to  nicotine. 

Scopola  atropoides,  containing  hyoscyamine  and  hyoscine,  and  perhaps  small 
quantities  of  atropine. 

1  The  relative  proportion  of  atropine  and  hyoscyamine  in  all  these  plants  is  not 
known,  as  hyoscyamine  is  very  often  changed  to  atropine  in  the  process  of  extraction. 


278  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION, 

Mandragora  autumnalis,  or  Atropa  mandragora  (Mandrake),  containing  hyos- 
cyamine  with  traces  of  other  alkaloids. 

A  number  of  other  Solanacese — e.  g.,  tobacco  and  potato  leaves,  are  said 
to  contain  small  quantities  of  one  or  other  of  these  alkaloids  but  the 
quantity  present  here  is  too  small  to  be  of  any  importance.  A  ptomaine 
formed  by  the  decomposition  of  fish  and  meat  and  known  as  ptomatropine 
also  produces  symptoms  closely  resembling  those  of  atropine  poisoning,  but 
has  not  been  isolated  as  yet. 

These  alkaloids  all  resemble  each  other  closely  in  the  effects  pro- 
duced by  them  in  animals.  Some  differences  in  the  symptoms  exist, 
however,  and  the  action  of  atropine  alone  will  first  be  described  and 
later  the  points  in  which  that  of  hyoscyamine  and  of  hyoscine  differ 
from  it. 

Atropine  acts  as  a  stimulant  to  the  central  nervous  system  and 
paralyzes  the  terminations  of  a  number  of  nerves,  more  especially  those 
that  supply  involuntary  muscle,  secretory  glands  and  the  heart. 

Symptoms.  —  In  man  and  the  higher  animals  small  toxic  doses  cause 
dryness  of  the  skin  and  throat,  thirst,  difficulty  in  swallowing  and 
hoarseness  in  speaking.  There  is  often  nausea  and  in  some  cases 
vomiting,  headache  and  giddiness ;  the  pupils  are  wider  than  normal 
and  the  sight  may  be  indistinct,  especially  for  near  objects.  The  res- 
piration and  pulse  are  quickened,  or  the  latter  may  at  first  be  some- 
what slowed.  A  symptom  that  is  often  present,  though  by  no  means 
invariably  so,  is  redness  of  the  skin,  more  especially  of  the  head  and 
neck ;  the  conjunctiva  may  also  be  congested.  After  larger  doses 
the  same  symptoms  are  observed,  but  are  soon  followed  by  others  of 
graver  import.  The  patient  can  no  longer  swallow,  although  suffering 
from  intense  thirst,  the  heart  is  generally  extremely  rapid,  speech  is 
difficult  and  hoarse,  and  the  pupils  are  dilated  until  the  iris  almost  dis- 
appears. Restlessness  and  garrulity  point  to  an  increase  in  the  irri- 
tability of  the  brain ;  the  patient  at  first  talks  in  a  perfectly  normal 
way  but  soon  becomes  confused,  begins  a  sentence  and  does  not  finish 
it,  often  bursts  into  laughter  or  tears,  and  in  short  becomes  delirious 
and  eventually  maniacal.  Often  marked  tremor  of  different  muscles 
may  be  observed,  and  eventually  convulsions  set  in  and  may  be  the 
cause  of  death  through  the  failure  of  the  respiration.  As  a  general 
rule,  however,  the  stage  of  excitement  passes  into  one  of  depression, 
the  patient  sinks  into  a  sleep,  which  deepens  into  stupor  and  coma, 
the  respiration  and  heart  become  slow,  weak  and  irregular,  and  death 
eventually  occurs  from  asphyxia. 

In  the  frog  the  injection  of  small  quantities  of  atropine  is  followed  by 
a  stage  of  increased  reflex  excitability,  exactly  resembling  that  seen  under 
strychnine.  It  is  generally  of  short  duration,  however,  and  is  followed 
by  a  stage  in  which  the  frog  lies  motionless  and  does  not  react  to  stim- 
ulation in  any  way.  After  a  variable  time,  sometimes  a  few  hours, 
oftener  several  days,  a  return  of  the  first  symptom  occurs,  the  reflex 
being  much  exaggerated  and  the  tonic  convulsions  described  under 
strychnine  being  generally  developed.  This  stage  slowly  passes  off 
and  the  animal  again  becomes  normal. 


ATROPINE  SERIES.  279 

Action. — These  symptoms  both  in  mammals  and  amphibians  indi- 
cate stimulation  of  the  Central  Nervous  System  followed  by  depression. 
Those  observed  in  man  sometimes  resemble  those  seen  in  the  excite- 
ment stage  of  alcoholic  poisoning,  and  it  has  been  suggested  that  in 
both  the  cause  is  rather  a  lessening  of  the  control  normally  exercised 
by  the  higher  powers  over  the  lower  motor  areas  than  a  true  stimula- 
tion of  the  latter.  But  this  is  shown  to  be  incorrect  by  the  fact 
that  in  atropine  poisoning  the  motor  area  is  more  easily  stimulated 
by  the  electric  current  than  normally.  The  stimulant  action  of  atro- 
pine is  also  seen  in  the  increased  reflex  response  to  irritation  of  the 
skin,  as  well  as  in  the  augmented  activity  of  the  centres  in  the  medulla. 
The  nervous  symptoms  under  atropine,  therefore,  arise  from  true  stim- 
ulation of  the  central  nervous  system,  but  they  are  wholly  different  1 
from  those  produced  by  strychnine,  because  the  latter  acts  more  espe- 
cially on  the  lower  parts  of  the  nervous  axis,  while  atropine  acts  more 
strongly  on  the  higher  divisions.  The  most  marked  symptoms  of 
strychnine  poisoning  arise  from  the  spinal  cord  and  medulla  oblongata, 
and  consist  in  increased  reflex  movements  and  convulsions,  while 
those  caused  by  atropine  are  rather  to  be  referred  to  the  brain,  and 
consist  in  increased  coordinated  movements,  such  as  talking  and 
delirium,  the  exaggerated  reflex  being  of  minor  importance.  In  the 
frog  the  same  effects  are  produced  by  each,  because  the  higher 
parts  of  the  central  nervous  system  being  less  developed  than  in  the 
mammals,  the  first  symptoms  produced  are  those  arising  from  the  cord. 
Atropine  differs  from  caffeine,  on  the  other  hand,  in  its  effect  on  the 
brain,  for  under  the  latter  the  psychical  functions  are  those  affected^ 
first  of  all.  It  would  seem  probable,  then,  that  each  of  these  three  j 
stimulates  the  whole  of  the  central  nervous  system  more  or  less,  but: 

;  that  while  strychnine  acts   more  strongly  on  the  lojvyer^di  visions,  the? 
spinal  cord  and  medulla,  and   oaffei ne,  on   the  highest  functions^  the. 

_4>sychical,  atrooine  ^occupies  a  midway  position,  and  exercises  its  chiefs 
action  on  the  motor  divisions  of  the  brain.  These  are  rendered  so  ex- 
citable that  the  controlling  areas  can  no  longer  keep  them  in  check,  and 
an  increase  in  movement  occurs  somewhat  resembling  that  seen  when 
the  controlling  areas  are  paralyzed  by  alcohol.  The  stimulant  action 
spreads  downwards  when  large  quantities  have  been  absorbed,  and 
involves  the  medulla  oblongata  and  spinal  cord,  so  that  symptoms 
resembling  those  seen  in  strychnine  poisoning  may  make  their  ap- 
pearance. After  the  stimulation  has  lasted  some  time,  depression  sets 
in  and  may  go  on  to  complete  paralysis  of  the  central  nervous  system. 
This  is  fatal  to  mammals  through  cessation  of  the  respiration,  but  in 
the  amphibia  the  paralysis  may  pass  off  after  some  time  as  the  poison 
is  excreted,  and  the  stage  of  stimulation  is  renewed.  Even  during  the 
stimulation  stage  some  symptoms  of  depression  are  to  be  made  out, 
exactly  as  has  been  described  under  strychnine. 

The  peripheral  action  of  atropine  involves  a  number  of  secretory 

glands,  the  organs  containing  unstriped  muscular  tissue  and  the  heart. 

Most  of  the  Secretions  are  decreased  by  the  application  of  atropine 


280  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

— salivary,  mucous,  milk  and  sweat.  This  is  due  not  to  any  action 
upon  the  secretory  cells,  but  to  paralysis  of  some  of  the  nerve  ends. 
It  has  been  investigated  most  carefully  in  the  salivary  glands,  but 
enough  work  has  been  done  on  the  others  to  show  that  the  process 
is  the  same  in  all.  The  secretion  of  saliva  in  the  normal  animal  seems 
to  occur  only  when  impulses  reach  the  gland  cells  by  one  of  two  paths 
—  through  the  chorda  tympani,  or  through  the  cervical  sympathetic 
fibres.  If  the  chorda  tympani  be  divided  and  put  on  electrodes  and  a 
canula  be  passed  into  Wharton's  duct,  a  rapid  flow  occurs  through  it 
on  stimulation  of  the  nerve,  which  ceases  or  is  very  much  diminished 
on  stopping  the  stimulation.  If  now  atropine  be  injected,  stimulation 
causes  no  increase  in  the  secretion  and  atropine,  therefore,  seems  to 
paralyze  some  part  of  the  peripheral  secretory  apparatus.  The 
chorda  tympani  passes  through  ganglion  cells  on  its  way  to  the  gland 
cells,  and  the  impulses  might  be  hindered  in  their  passage  through 
these,  as  actually  occurs  under  the  action  of  some  drugs.  (See  Nico- 
tine.) But  this  is  not  the  explanation  of  the  inefficiency  of  chorda 
stimulation,  as  is  shown  by  the  fact  that  if  the  electrodes  be  pushed 
into  the  hilus  of  the  gland  so  as  to  stimulate  the  nerve  fibres  beyond 
the  ganglia  no  secretion  follows.  Another  explanation  would  be  that 
the  gland  cells  themselves  are  paralyzed  by  atropine,  but  this  is  shown 
not  to  be  the  case,  for  on  stimulating  the  sympathetic  which  supplies 
the  same  cells  as  the  chorda  tympani,  the  usual  secretion  follows.  The 
site  of  action  of  atropine,  therefore,  seems  to  lie  between  the  ganglion 
cells  on  the  course  of  the  chorda  tympani  and  the  secretory  cells,  that  is, 
the  point  of  attack  is  the  terminations  of  the  nerve  fibres  in  the  gland 
cells.  The  action  is  limited  to  certain  definite  terminations,  for  it  has 
been  noted  already  that  the  sympathetic  secretory  fibres  are  not  par- 
alyzed, and  it  was  discovered  by  Heidenhain  that  not  all  the  fibres  of 
the  chorda  tympani  are  acted  on  by  atropine.  On  stimulation  of  this 
nerve  in  the  unpoisoned  animal,  besides  the  increased  secretion,  a  red- 
ness and  swelling  of  the  gland  is  noticed,  its  temperature  rises,  and  the 
blood  escapes  from  the  veins  in  much  larger  quantity  than  usual  and 
in  spurts  as  if  from  an  artery.  This  is  due  to  the  dilation  of- the 
arterioles  of  the  gland  from  the  stimulation  of  vaso-dilator  fibres 
which  run  along  with  the  secretory  fibres  in  the  chorda  tympani. 
These  fibres  are  not  paralyzed  by  an  injection  of  atropine,  for  on  stim- 
ulation of  the  chorda  afterwards  the  same  symptoms  are  produced  as 
before,  save  that  no  secretion  occurs.  Atropine  then  seems  to  select 
the  terminations  of  the  secretory  fibres  of  the  chorda  tympani  for 
paralysis  and  to  leave  all  others  unaffected.  The  secretion  of  saliva 
seems  to  occur  generally  only  on  the  arrival  of  impulses  by  way  of  the 
chorda  tympani,  so  that  on  the  paralysis  of  its  terminations  the  secre- 
tion ceases  entirely. 

In  the  same  way  the  other  glands  of  the  mouth,  throat,  nose  and  res- 
piratory passages  cease  secreting  after  atropine,  and  the  eifect  is  the  char- 
acteristic dryness  of  the  mouth,  the  hoarseness  of  the  voice,  and  the 
thirst  and  difficulty  in  swallowing  complained  of  after  its  administration. 


ATROPINE  SERIES.  281 

The  secretion  of  the  gastric  juice  has  recently  been  shown  to  be 
diminished  or  entirely  arrested  by  atropine,  which  paralyzes  the  termi- 
nations of  the  secretory  fibres  of  the  pneumogastric  nerve  in  the  stomach. 
The  hydrochloric  acid  of  the  secretion  is  more  reduced  than  either  the 
pepsin  or  the  fluid  as  a  whole.  The  pancreatic  secretion  may  be 
induced  either  by  nervous  impulses  reaching  it  by  the  fibres  of  the 
pneumogastric,  or  by  the  secretion  formed  in  the  intestinal  epithelium 
being  carried  to  it  by  the  bloodvessels ;  atropine  paralyzes  the  termina- 
tions of  the  pneumogastric  so  that  no  secretion  arises  from  its  stimulation, 
but  the  intestinal  secretion  acts  directly  on  the  pancreatic  cells  so  that  the 
gland  continues  to  respond  to  its  presence.  The  bile  is  also  said  to  be 
somewhat  lessened  by  atropine.  The  production  of  sugar  from  the  gly- 
cogen  of  the  liver  has  been  recently  shown  to  be  controlled  by  branches  \ 
\  of  the  coeliac  plexus,  but  these  have  no  effect  after  atropine,  so  that  the 
terminations  of  the  nerves  in  the  liver  cells  seem  to  be  paralyzed  also.  } 

The  same  paralysis  is  produced  in  the  terminations  of  the  nerves  in 
the  siueat  glands.  Stimulation  of  the  sciatic  nerve  as  a  general  rule 
produces  perspiration  in  the  foot  of  the  cat  and  dog,  but  after  atropine 
this  effect  is  absent,  because  the  impulses  cannot  reach  the  cells  through 
the  paralyzed  terminations,  and  the  skin  therefore  becomes  dry  and 
hot.  The  secretion  of  milk  bears  the  same  relation  to  that  of  per- 
spiration as  that  of  the  pancreatic  juice  does  to  the  saliva ;  it  is 
increased  by  stimuli  from  the  central  nervous  system,  but  at  the 
same  time  the  mammary  gland  continues  to  secrete  after  all  its  nerves 
have  been  divided.  Atropine  therefore  lessens  the  secretion  by  para- 
lyzing its  nerves,  but  does  not  stop  it  altogether.  The  solids  of  the 
milk  seem  rather  increased  than  diminished  by  the  drug. 

The  kidney  is  not  controlled  so  directly  by  nervous  influences  as  the 
glands  hitherto  discussed,  and  atropine  causes  little  or  no  change  in  the 
amount  of  urine  except  what  is  probably  the  indirect  result  of  the  arrest 
of  the  other  secretions.  The  secretion  of  lymph  is  not  altered  by  atro- 
pine, so  that  it  is  probably  not  controlled  by  nerves  in  the  same  way 
as  the  true  secretions. 

All  Organs  Containing  Unstriped  Muscle  (apart  from  the  arterial 
wall)  seem  to  be  altered  by  atropine.  Thus  the  movements  of  the 
stomach,  intestine,  bladder,  uterus,  spleen,  thoracic  duct,  and  of  the 
pupil  and  oesophagus  (except  in  animals,  in  which  these  consist  of 
striped  muscle)  are  lessened  by  atropine. 

Atropine  has  generally  a   sedative   effect  on  the  movements  of  the 

stomach  and  intestine,  though  vomiting  is  not  infrequently  observed  in 

cases  of  poisoning,  and  less   often  free  evacuation  of  the  contents  of 

the  bowel.     The   increased   movement    induced   by  ordinary  doses  of 

-:  the  purgatives  is   not  arrested,  but  the   griping  pains  resulting  from  ] 

;  large  doses  or  from  the  more   violent  purgatives   are  absent   or   less,: 

marked  if  atropine  is  given  along  with  them.     Similarly,  the  violent 

peristaltic  and  tetanic   contractions  seen  after  such  poisons  as  nicotine 

and  muscarine  are  prevented  by  the  preliminary  injection  of  atropine. 

These  results  were  formerly  explained  by  supposing  that  atropine  para- 


282  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

lyzed  the  terminations  of  the  extrinsic  motor  nerve  of  the  bowel  in 
the  same  way  as  it  paralyzes  the  terminations  of  the  chorda  tympani. 
But  Bayliss  and  Starling  and  Dixon  have  recently  shown  that  atropine 
does  not  alter  the  effect  of  stimulation  of  the  vagus,  the  motor  nerve 
of  the  intestine  and  stomach,  nor  of  that  of  the  splanchnic,  the  inhibi- 
tory nerve.  The  fact  that  it  antagonizes  the  excessive  movement  after 
these  poisons  cannot  be  attributed  to  action  on  the  terminations  of 
these  nerves,  therefore,  and  no  other  explanation  of  the  unquestion- 
able effect  of  atropine  on  the  stomach  and  bowel  has  been  vouchsafed. 
It  appears  possible  that  atropine  acts  on  some  still  unknown  nerve 
terminations,  and  that  the  violent  movements  which  it  arrests  arise 
from  stimulation  of  a  mechanism  which  is  distinct  from  that  presiding 
over  the  ordinary  peristalsis. 

Atropine  exercises  the  same  sedative  effect  on  the  movements  of  other 
organs  as  on  those  of  the  bowel.  Thus,  the  spleen,  uterus,  bladder,  and 
the  bronchial  muscles  seem  less  liable  to  contraction  after  its  use.  In 
regard  to  its  action  on  the  two  first  but  little  is  known,  but  Dreser  has 
shown  that  the  stimulation  of  the  pneumogastric  does  not  cause  con- 
traction of  the  bronchial  muscle  after  atropine,  while  in  the  unpoisoned 
animal  it  has  this  effect.  In  regard  to  the  bladder  it  has  been  observed 
frequently  in  cases  of  poisoning  that  the  urine  is  ejected  soon  after  the 
ingestion  of  the  poison,  and  subsequently  there  is  a  desire  to  micturate 
without  the  ability  to  do  so.  The  preliminary  contraction  of  the  blad- 
der would  seem  analogous  to  that  of  the  intestine,  and  the  subsequent 
inability  to  empty  it  to  the  diminution  of  the  peristalsis.  The  rhyth- 
mical contractions  of  the  ureters  are  said  to  be  accelerated  by  small 
doses,  but  to  be  slowed  and  arrested  by  larger  amounts. 

-The  terminations  of  the  nerves  in  the  unstriped  muscle  of  the 
oesophagus  seem  to  be  affected  in  the  same  way  as  in  that  of  the  intes- 
tine. A  curious  contrast  has  been  noted  by  Luchsinger  in  the  behavior 
of  the  oesophagus  in  rabbits  and  cats,  in  the  former  of  which  the  mus- 
cle is  striated,  while  in  the  latter  the  upper  part  is  striated,  the  lower 
is  unstriated.  Atropine,  he  found,  paralyzes  the  vagus  terminations  in 
those  parts  which  are  unstriped,  while  leaving  unaffected  those  in  the 
striped  fibres.  Exactly  the  opposite  occurs  after  curara,  which  para- 
lyzes the  nerve  supply  of  the  striped  muscle,  while  leaving  the  unstriped 
active.  Here,  again,  is  evidence  of  the  selective  power  of  these  poisons 
and  of  the  difference  in  the  chemical  composition  of  nearly  related 
structures. 

It  is  possible  that  the  difficulty  in  swallowing,  which  is  so  well 
marked  in  cases  of  poisoning  by  atropine,  may  be  due  in  part  to  the 
paralysis  of  the  motor  nerve  ends,  but  it  is  generally  attributed  to  the 
absence  of  the  mucous  secretion  and  consequent  dryness  of  the  pas- 
sages. 

The  dilatation  of  the  pupil  by  atropine  has  been  the  subject  of  a 
very  large  number  of  researches  both  by  physiologists  and  by  practical 
ophthalmologists.  It  occurs  on  internal  administration  as  well  as  on 
the  application  of  minute  quantities  locally,  and  is  due  to  paralysis  of 


ATROPINE  SERIES. 


283 


the  terminations  of  the  motor  nerve  in  the  circular  muscle  of  the  iris. 
This  is  shown  by  the  fact  that  stimulation  of  the  motor  oculi  nerve  or 
of  the  sympathetic  neuron  running  from  the  ciliary  ganglion  is  without 
effect,  as  well  as  that  the  dilatation  may  be  produced  by  atropine  in 
the  excised  eye.  This  limits  the  paralysis  to  the  periphery,  and  that 
the  muscle  is  not  acted  on  is  shown  by  its  reacting  to  electrical  stimu- 
lation. The  local  nature  of  the  action  may  be  further  shown  by  care- 
fully applying  a  minute  quantity  of  the  drug  to  one  side  of  the  cornea, 
when  dilatation  of  one  half  or  less  of  the  pupil  occurs,  the  rest  remain- 
ing contracted.  The  motor  oculi  (Fig.  26)  constantly  transmits  im- 
pulses through  the  ciliary  nerves  to  the  sphincter  muscle  of  the  iris  and 
keeps  the  pupil  moderately  contracted,  and  when  these  impulses  can 
no  longer  reach  the  iris  owing  to  the  paraJysis  of  the  nerve  ends,  the 

FIG.  26. 


Diagram  of  the  innervation  of  the  iris.  P,  a  fibre  of  the  motor  oculi  passing  from  the  brain  to  the 
ciliary  ganglion  (JV)  in  which  it  terminates  around  a  nerve  cell,  which  sends  an  axis  cylinder  to  ter- 
minate M,  in  the  circular  fibres  of  the  iris.  R,  a  spinal  nerve  fibre  issuing  from  the  lower  cervical 
cord,  running  through  the  stellate  and  inferior  cervical  ganglia  and  terminating  around  a  ganglion 
cell  in  the  superior  cervical  ganglion,  G.  The  axis  cylinder  from  this  nerve  cell  runs  to  the  iris  (pass- 
ing the  ciliary  ganglion)  and  terminates,  C,  on  the  radiating  fibres.  M  indicates  the  terminations  of 
the  nerve  fibre  in  the  circular  fibres,  and  is  the  point  acted  on  by  atropine  and  muscarine.  NN' 
the  ganglion  cells,  is  the  seat  of  action  of  nicotine.  C,  the  terminations  in  the  dilator  fibres,  that  of 
cocaine. 

sphincter  relaxes  and  the  pupil  dilates.  The  muscle  itself  does  npi 
seem  to  be  affected  by  the  ordinary  application  of  atropine,  but  if 
strong  solutions  be  continuously  applied,  its  fibres  may  be  paralyzed 
by  it  as  by  many  other  drugs.  The  action  in  paralyzing^  the  nerve 
end  is  universally  accepted  now,  although  it  was  formerly  disputed. 


284  ORGANIC  DRUGS  ACTING  AFTE&  ABSORPTION. 

A  farther  question  is  whether  this  is  the  only  effect  of  atropine  on  the 
pupil,  or  whether  the  terminations  of  the  dilating  sympathetic  fibres  are  not 
stimulated  at  the  same  time,  and  this  cannot  as  yet  be  said  to  be  generally 
agreed  upon,  although  there  is  very  strong  evidence  against  the  latter  view. 
Its  advocates  have  generally  ignored  the  fact  that  the  constrictor  muscle  is 
constantly  opposed  by  dilator  fibres,  and  that  when  the  former  is  thrown  out 
of  activity  by  the  paralysis  of  the  terminations  of  the  motor  oculi,  the  radiat- 
ing fibres  cause  an  active  dilatation  without  any  stimulation  of  the  nerve  ends 
being  necessary.  If,  however,  the  radiating  muscular  fibres  be  separated 
from  their  innervating  centre  by  section  of  the  cervical  sympathetic  nerve 
in  the  neck,  they  also  cease  to  contract  and  there  is  no  active  dilatation,  so 
that  atropine  causes  less  widening  of  the  pupil  than  it  would  if  impulses 
continued  to  reach  the  radiating  muscle.  After  the  application  of  atropine 
to  the  eye,  the  iris  often  relaxes  with  sufficient  force  to  tear  weak  adhesions 
to  the  lens,  and  this  has  also  been  held  to  indicate  that  the  dilator  fibres  are 
stimulated,  for  it  is  unlikely  that  the  mere  passive  relaxation  of  the  iris  could 
rupture  an  attachment.  Similarly,  if  the  iris  be  attached  at  two  points  to  the 
lens,  atropine  causes  a  bow-shaped  dilatation  between  them,  the  concavity  being 
directed  inward,  whereas  if  the  dilatation  were  purely  passive  the  part  between 
the  points  of  attachment  would  probably  be  loose  and  wrinkled.  The  dilatation 
is  unquestionably  an  active  movement,  accomplished  by  the  contraction  of  the 
radiating  muscular  fibres,  but  these  are  not  put  in  motion  by  stimulation  of  the 
terminations  of  the  fibres  in  the  radiating  muscles  of  the  iris,  but  by  the  normal 
impulses  descending  from  the  central  nervous  system,  which  aiter  atropine  are 
not  counterbalanced  by  impulses  reaching  the  circular  fibres. 

In  short,  the  evidence  goes  to  prove  that  atropine  dilates  the  pupil 
\   by  paralyzing  the  terminations  of  the  nerves  in  the  circular  muscle. 

•  This  leaves  the  radiating  fibres  unopposed,  and  they  therefore  draw 
Back  the  edge  of  the  iris.     The  terminations  of  the  nerves  in  the  radi- 

*  ating  muscle  fibres  do  not  seem  to  be  affected  by  atropine. 

The  dilatation  of  the  pupil  effected  by  atropine  is  not  quite  maximal, 
vfor  stimulation  of  the  cervical  sympathetic  trunk  generally  increases  it, 
though  but  slightly.  It  differs  considerably  in  different  animals,  be- 
ing more  complete  in  man,  the  dog,  and  the  cat  than  in  the  rabbit, 
entirely  absent  in  birds  and  reptiles  and  elicited  with  difficulty  in  the 
frog.  In  birds  and  reptiles  the  iris  consists  of  striped  muscle  fibres, 
and  accordingly  atropine  has  no  action  on  the  nerve  terminations. 

In  the  rabbit  and  in  man  the  dilatation  is  sometimes  preceded  by  a 
slight  contraction  due,  it  is  believed,  to  an  irritant  preparation  setting 
up  a  reflex  from  the  conjunctival  sensory  nerves.  When  complete  dila- 
tation is  attained,  the  pupil  ceases  to  contract  in  bright  light,  as  the 
impulses  descending  from  the  central  nervous  system  are  prevented 
from  reaching  the  muscle,  although  the  rest  of  the  reflex  arc  is  intact. 
According  to  several  observers  the  pupil  dilated  by  atropine  contracts 
during  narcosis  from  chloroform  or  chloral,  but  this  statement  requires 
further  confirmation. 

Besides  the  dilatation  of  the  pupil,  a  further  result  of  the  applica- 
tion of  atropine  to  the  eye  is  the  paralysis  of  the  accommodation.  Near 
objects  are  no  longer  seen  clearly,  while  distant  ones  are  as  distinct  as 
formerly  or  may  be  even  more  distinct  in  some  eyes.  The  action  is 
here  again  on  the  terminations  of  the  motor  nerve,  in  this  case  in  the 
ciliary  muscle.  On  local  application  the  relaxation  of  the  lens  occurs 


ATROPINE  SERIES. 


285 


later,  and  disappears  earlier  than  the  dilatation  of  the  pupil,  and 
larger  quantities  are  required  to  produce  it.. 

The  intraocular  pressure  undergoes  a  considerable  augmentation  after 
the  local  application  of  atropine  as  well  as  when  it  is  applied  through 
the  general  circulation.  This  seems  to  be  due  to  the  dilatation  of  the 
pupil,  although  some  writers  seem  to  believe  that  atropine  has  also  a 
special  action  on  the  intraocular  fluids.  The  increase  in  the  intra- 
ocular pressure  has  been  demonstrated  in  animals  through  the  move- 
ments of  a  manometer  communicating  with  the  vitreous  humor,  and  is 
a  well-known  result  of  the  application  of  atropine  in  ophthalmology. 
It  may,  perhaps,  explain  the  pain  and  aching  in  the  eye  and  the  head- 
ache complained  of  in  some  cases  of  poisoning,  while  in  others  these 
may  be  due  to  bright  light  falling  on  the  retina,  which  is  unprotected 
by  the  iris. 

Atropine  paralyzes  the  Inhibitory  Terminations  of  the  Vagus  in  the 
Heart,  and  stimulation  of  this  nerve  therefore  causes  no  changes  in 
the  pulse  after  its  administration.  A  number  of  other  drugs  also 
remove  the  inhibitory  power  of  the  vagus,  but  act  on  a  different  part 
of  the  nerve,  namely,  on  the  ganglia.  That  atropine  does  not  act  here 
but  on  the  terminations,  has  been  shown  by  a  number  of  observations. 

FIG.  27. 


Tracings  of  the  ventricle  (lower)  and  auricle  (upper)  of  the  dog's  heart.  During  systole  the 
levers  move  upwards  ;  during  diastole,  downwards.  At  A,  the  heart  is  normal  ;  at  B,  the  inhibitory 
fibres  were  stimulated  electrically,  and  this  was  continued  throughout  the  tracing.  The  ventricular 
rhythm  became  slow  and  irregular,  while  the  auricle  stood  still  in  diastole.  At  C,  atropine  sulphate 
was  injected  into  a  vein,  and  at  D  the  effects  of  the  inhibition  began  to  pass  off,  although  the  stimula- 
tion was  continued. 

Thus,  in  the  normal  frog's  heart,  and  even  after  paralysis  of  the  gan- 
glia on  the  course  of  the  vagus,  electrical  stimulation  of  the  venous 
sinus  causes  slowing  and  standstill  of  the  heart,  because  the  stimulus 
reaches  the  vagus  beyond  the  paralyzed  ganglia  (Fig.  24,  p.  267) ;  but 
after  atropine,  no  slowing  follows  stimulation  of  the  sinus.  Again, 
several  drugs  stimulate  the  ends  of  the  vagus  in  the  heart  and  act  on 
parts  in  which  no  ganglia  exist,  but  these  drugs  have  no  effect  whatever 
after  atropine.  Small  quantities  of  atropine  have  no  further  action  on 
the  heart  than  the  paralysis  of  the  inhibitory  nerve  ends.  The  ter- 
minations of  the  accelerator  nerve  are  unaffected,  exactly  as  the  ter- 
minations of  the  sympathetic  in  the  salivary  glands,  and  the  heart  mus- 
cle is  neither  stimulated  nor  depressed.  The  heart  is  therefore  placed 


286  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

in  the  same  position  as  if  the  vagus  were  divided  in  the  neck,  and,  ac- 
cordingly, is  accelerated  in  some  animals,  while  in  others  the  rhythm  is 
unchanged.  In  the  dog  there  is  a  marked  quickening  of  the  heart  after 
atropine,  because  normally  impulses  are  constantly  transmitted  from 
the  inhibitory  centre  in  the  medulla,  and  these  prevent  the  heart  from 
beating  as  rapidly  as  it  would  if  freed  from  the  nervous  control.  In 
the  cat  the  "  tone  "  of  the  vagus  is  less,  and  the  changes  produced  by 
atropine  are  correspondingly  smaller,  while  in  the  rabbit  and  frog  there 
is  generally  no  inhibitory  retardation  of  the  heart,  and  atropine  therefore 
produces  little  change.  In  man  the  eifects  vary  considerably  with  the 
age  of  the  patient.  The  inhibitory  fibres  seem  almost  inactive  at  birth, 
but  their  tone  increases  with  age  up  to  25-35  years,  and  from  this 
time  lessens  again  and  is  very  slight  in  old  age.  Atropine  does  not 
quicken  the  heart  in  the  newborn  child,  but  up  to  about  30  the  accel- 
eration increases  with  the  age,  and  from  this  point  onwards  it  lessens 
again  until  the  heart  is  accelerated  by  only  4—5  beats  per  minute  in 
patients  between  80-90  years.  Along  with  the  acceleration  of  the 
pulse  the  other  eifects  of  vagus  section  are  also  produced  —  increase  in 
the  extent  of  systole,  decrease  in  the  diastole  and  augmentation  of  the 
output  of  the  heart  per  minute. 

Stimulation  of  the  vagus  causes  no  retardation  of  the  pulse  after  atropine, 
but  on  the  contrary,  is  not  infrequently  followed  by  acceleration  from  the 
presence  of  accelerator  fibres  which  are  not  affected  by  atropine. 

Large  quantities  of  atropine,  besides  paralyzing  the  vagus,  weaken  and 
depress  the  heart  muscle  and  the  contractions  consequently  become  slower 
and  weaker  and  the  output  of  the  heart  is  less  than  normal.  Hedbom 
states  that  large  quantities  accelerate  the  coronary  circulation  in  mammals 
and  increase  the  amplitude  of  the  contractions.  He  is  inclined  to  regard  the 
latter  alteration  as  due  in  part  to  the  dilatation  of  the  coronary  vessels,  in 
part  to  a  direct  action  on  the  heart  muscle. 

The  peripheral  action  of  atropine  hitherto  discussed  is  due  to  its  para- 
lyzing the  terminations  of  a  number  of  nerves  in  small  doses  and  to  its 
paralyzing  the  muscle  or  gland  cells  when  administered  in  very  large  quan- 
tities. These  facts  are  generally  accepted  as  true,  but  a  number  of  further 
effects  have  been  disputed  and  may  now  be  shortly  discussed. 

It  is  not  seldom  stated  that  atropine,  in  addition  to  paralyzing  the  vagus 
ends,  stimulates  the  heart  muscle  and  thereby  quickens  its  rhythm.  This 
assertion  is  somewhat  difficult  to  disprove,  but  none  of  the  alleged  facts 
brought  forward  to  support  it  have  stood  closer  investigation.  The  error 
generally  arose  from  the  belief  that  atropine  acted  on  the  ganglia  and 
not  on  the  nerve  ends  or  from  the  use  of  impure  and  irritant  preparations, 
and  all  the  phenomena  on  which  it  was  based  may  be  explained  by  the 
more  modern  theory  that  the  ganglia  on  the  course  of  the  inhibitory  nerve 
fibres  are  left  intact  by  atropine,  while  the  terminations  of  the  nerve  are 
paralyzed. 

A  further  question  is  whether  the  nerve  ends  are  paralyzed  at  once  or 
whether  they  undergo  a  short  stimulation  first.  In  favor  of  the  latter 
theory  several  facts  may  be  mentioned,  as  that  the  heart  in  mammals  is 
often  first  slowed  and  then  quickened  by  atropine.  This  might  indicate  stimu- 
lation of  the  nerve  ends,  but  seems  due  rather  to  the  inhibitory  centre  in 
the  medulla  being  stimulated  before  the  terminations  are  paralyzed.  This 
stimulation  of  the  centre  slows  the  heart  until  the  impulses  sent  out  from  it 
are  prevented  from  reaching  the  organ  by  paralysis  of  the  nerve  ends.  The 
increase  in  the  intestinal  movements,  which  occurs  immediately  after  the 


ATROPINE  SERIES.  287 

injection  of  atropine,  might  also  be  cited  as  proof  of  the  preliminary  stimu- 
lation of  the  nerve  ends,  but  may  also  be  explained  by  the  inhibitory 
terminations  being  paralyzed  earlier  than  the  motor,  so  that  these  have  a 
brief  period  of  unrestrained  activity.  In  the  eye  a  short  stage  of  contraction 
of  the  pupil  not  infrequently  precedes  the  dilatation,  but  it  is  generally 
believed  to  be  due  to  a  reflex  from  the  application  of  an  irritant  solution  to 
the  conjunctiva.  Lastly,  when  atropine  is  applied  to  the  eye  of  the  cat  a 
considerable  secretion  of  saliva  almost  always  follows  for  a  short  time,  and 
this  might  be  held  to  indicate  a  stimulation  of  the  terminations  of  the  chorda. 
It  is  more  likely,  however,  that  it  is  a  reflex  secretion  from  the  bitter  taste 
of  the  alkaloid  which  has  escaped  through  the  lachrymal  duct  into  the  back 
of  the  throat. 

Several  alkaloids  stimulate  the  same  peripheral  nerve  terminations 
as  atropine  paralyzes,  and  the  interaction  of  the  two  groups  is  of  con- 
siderable importance.  It  is  more  profitably  discussed  after  the  general 
action  of  these  poisons  has  been  learned,  and  will  be  taken  up  at  that 
point  (see  rnuscarine,  pilocarpine,  and  physostigmine  ;  compare  also 
nicotine  and  the  curara  and  coniine  series). 

The  voluntary  Muscles  are  not  directly  affected  by  atropine.  The 
terminations  of  the  motor  Nerves  are  paralyzed  in  the  frog  by  large 
doses,  but  this  has  not  been  elicited  in  mammals  by  ordinary  meth- 
ods of  experimental  investigation.  The  terminations  of  the  sensory 
nerves  are  paralyzed,  or  at  any  rate  depressed  by  its  local  application. 
Thus  when  a  liniment  or  ointment  containing  atropine  is  applied  to 
the  skin,  a  numbness  of  the  part  is  produced  and  the  sensation  of  pain 
is  lessened.  The  local  anaesthetic  effect  is  not  elicited  by  its  internal 
administration,  although  it  is  said  that  the  frog  may  be  rendered  less 
sensitive  to  irritation  of  the  skin  if  poisoned  with  atropine.  Accord- 
ing to  some  recent  investigations  the  sensory  terminations  are  first 
stimulated  and  then  paralyzed,  but  the  assertion  stands  in  need  of  con- 
firmation. 

Circulation.  —  The  effect  of  atropine  on  the  circulation  is  somewhat 
complex,  as,  besides  the  action  on  the  heart,  that  on  the  central  nervous 
system  must  be  considered..  The  heart  is  sometimes  slowed  and  weak- 
ened at  first,  owing  to  the  stimulation  of  the  inhibitory  centre  in  the 
medulla  probably,  but  is  generally  quickened  from  paralysis  of  the  in- 
hibitory fibres  in  the  heart,  and  after  very  large  doses  is  weakened  by 
the  direct  action  on  the  muscle  fibre.  The  blood-pressure  is  consider- 
ably increased  by  the  augmented  output  of  the  accelerated  heart,  and 
also  owing  to  stimulation  of  the  vaso-constrictor  centre  in  the  medulla 
which  cign.tra.cts  the  arterioles^  in  the__abdom en .  The  constriction  of 
these  vessels  is  accompanied  by  a  dilation  of  the  arterioles  of  the  skin, 
and  perhaps  of  the  brain,  from  excitation  of  the  vaso-dilator  centre, 
so  that  the  blood  tends  to  flow  from  the  abdominal  cavity  to  the  more 
superficial  parts.  The  dilation  of  the  skin  vessels  is,  however,  insuf- 
ficient to  counteract  altogether  the  contraction  of  those  of  the  abdomen, 
so  that  a  considerable  increase  in  the  arterial  tension  follows  the  in- 
gestion  of  atropine.  The  increased  pressure  is  maintained  for  some 
time  after  small  doses,  while  large  ones  lower  it  from  the  action  on 
the  heart  muscle.  The  dilation  of  the  skin  vessels  is  more  especially 


288  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

seen  in  the  head  and  neck,  and  here  produces  marked  flushing  and 
a  rash  somewhat  resembling  that  of  scarlet  fever.  That  it  is  due  to 
central  action  is  shown  by  the  fact  that  it  is  prevented  by  division  of 
the  sympathetic  trunk  in  the  neck.  The  rash  usually  disappears  after 
a  few  hours,  but  is  sometimes  followed  in  a  day  or  two  by  desquama- 
tion.  The  circulation  always  persists  after  the  respiration  has  ceased, 
and  its  failure  is  not  the  cause  of  death  therefore. 

The  action  of  atropine  on  the  Respiration  has  been  the  subject  of 
much  discussion  in  recent  years.  It  is  sometimes  slower  at  first  through 
some  unexplained  central  action  but  then  becomes  quicker,  and  ac- 
cording to  most  observers  also  deeper,  and  the  amount  of  air  inspired 
per  minute  is  considerably  increased.  This  is  due  to  stimulation  of 
the  respiratory  centre,  which  undergoes  the  same  changes  as  the  rest 
of  the  central  nervous  system.  After  large  doses  this  quickened 
breathing  is  frequently  interrupted  by  convulsive  movements,  and 
such  an  interruption  often  proves  to  be  final.  If  it  returns,  the  move- 
ments become  shallower  and  slower  in  the  stage  of  depression  of  the 
nervous  centres,  and  the  failure  of  the  respiration  is  the  cause  of  death 
in  fatal  cases  of  poisoning. 

Atropine  often  induces  a  marked  rise  in  Temperature,  the  cause  of 
which  cannot  be  said  to  be  definitely  known.  According  to  Ott  the 
dissipation  of  heat  is  increased,  but  the  heat  formation  undergoes-  a 
still  greater  augmentation.  This  seems  to  be  independent  of  the  cir- 
culatory changes  and  also  of  the  convulsions,  and  is  attributed  by  him 
to  direct  action  on  the  heat  centres  of  the  brain. 

Atropine  is  Excreted  in  the  urine  in  small  quantities  when  injected 
into  the  dog,  but  most  of  it  undergoes  complete  oxidation  in  the  tissues  ; 
in  the  rabbit  this  seems  to  be  the  fate  of  the  whole  of  the  drug,  for 
none  is  found  in  the  excretions.1  Young  animals  withstand  much  larger 
quantities  than  adults,  according  to  v.  Anrep  because  the  brain  is  less 
highly  developed  and  the  cerebral  symptoms  are  therefore  produced 
less  easily.  Rabbits  may  be  fed  for  weeks  on  belladonna  leaves  exclu- 
sively without  showing  any  symptoms  of  poisoning,  while  carnivorous 
animals  and  man  are  very  much  more  sensitive  to  its  action.  A  curious 
case  of  poisoning  is  related  in  which  the  defence  was  made  that  the  alka- 
loid was  taken  accidentally  through  partaking  of  roast  rabbit,  the  ani- 
mal's flesh  having  been  saturated  with  atropine  through  feeding  on  bella- 
donna leaves.  It  was  found  that  rabbits  thus  fed  might,  in  fact,  con- 
tain large  quantities  of  atropine  and  yet  show  no  signs  of  poisoning. 
Von  Anrep  succeeded  in  developing  a  certain  degree  of  Tolerance  in 
dogs  through  repeated  administration  of  atropine,  but  it  was  very  in- 
complete. The  symptoms  arising  from  the  central  nervous  system 
were  much  less  evident  after  a  few  doses,  while  those  from  the  heart, 
pupil  and  secretory  glands  persisted  after  the  treatment  had  been  con- 
tinued for  some  time. 

Hyoscyamine  is  rarely  obtainable  in  pure  form,  as  it  is  almost  always 
mixed  with  atropine,  into  which  it  changes  when  kept  in  solution  and 

1  Traces  have  been  found  in  the  milk  of  some  animals  and  also  in  the  foetal  blood. 


ATROPINE  SERIES.  289 

perhaps  even  when  dry.  It  paralyzes  the  peripheral  terminations  of 
the  same  nerves  as  atropine,  but  acts  almost  exactly  twice  as  strongly 
on  them.  Its  action  on  the  central  nervous  system  in  mammals  | 
resembles  that  of  atropine  and  the  fatal  dose  is  the  same,  but  in  the 
frog  it  has  less  tendency  to  cause  convulsions.  No  narcotic  influence 
is  exercised  on  either  frogs  or  mammals ;  the  belief  that  it  induces 
sleep  is  founded  on  observations  in  which  hyoscine  was  mixed  with  the 
hyoscyamine  employed. 

The  action  of  atropine,  as  has  been  stated,  is  compounded  of  that  of  natu- 
ral or  laevorotary  hyoscyamine  with  that  of  its  dextrorotary  isomer.  The 
latter  does  not  exist  free  in  nature  and  possesses  only  a  feeble  action  on  the 
nerve  terminations,  while  it  stimulates  the  spinal  cord  of  the  frog  more  than 
either  atropine  or  hyoscyamine.  The  peripheral  action  of  atropine  is  thus  due 
to  its  containing  hyoscyamine,  and  as  a  grain  of  atropine  contains  only  half  a 
grain  of  hyoscyamine  the  former  naturally  exercises  only  half  the  effect  of  a 
grain  of  hyoscyamine.  On  the  other  hand,  the  half  grain  of  dextrorotary  hyoscy- 
amine in  a  grain  of  atropine  is  almost  inert  on  the  nerve  terminations,  but  exer- 
cises the  same  effect  on  the  central  nervous  system  as  its  Ia3vorotary  complement. 
Atropine  thus  acts  on  the  central  nervous  system  in  mammals  in  the  same 
strength  as  hyoscyamine,  but  only  half  as  strongly  in  the  periphery. 

Scopolamine,  or  Hyoscine,  resembles  atropine  closely  in  its  peripheral 
action.  The  inhibitory  terminations  in  the  heart  are  paralyzed, 
although  the  therapeutic  dose  in  man  is  too  small  to  elicit  this  effect 
and  the  pulse  is  therefore  unaltered  in  rate  or  may  be  slower  owing  to 
the  hypnotic  action.  It  produces  mydriasis  and  loss  of  accommoda- 
tion more  quickly  than  atropine,  but  for  a  much  shorter  time ;  pure 
hyoscine  acts  about  twice  as  strongly  on  the  nerve  terminations  as 
atropine,  or  about  equally  strongly  with  hyoscyamine.  The  effects  on 
the  central  nervous  system  present  the  greatest  divergences  from  those 
described  under  atropine,  for  the  characteristic  stimulation  is  absent  in 
the  great  majority  of  cases.  As  a  general  rule,  scopolamine  produces 
a  marked  sensation  of  fatigue  and  drowsiness,  and  the  patient  moves 
about  less  and  speaks  less.  Soon  an  overpowering  desire  to  sleep  is 
felt,  and  a  condition  in  no  way  dissimilar  to  the  natural  sleep  follows. 
In  many  cases,  however,  a  short  stage  of  excitement  with  giddiness, 
uncertain  movements,  and  difficult  and  indistinct  speech  precedes  sleep, 
and  occasionally  symptoms  exactly  resembling  those  produced  by  atro- 
piiie  follow  the  administration  of  hyoscine,  especially  if  large  doses 
are  employed.  Sleep  generally  lasts  from  5-8  hours,  and  the  patient 
may  then  remain  in  a  somnolent  condition  for  several  hours  longer. 
As  a  general  rule,  after  small  doses  no  confusion  is  complained  of  on 
awakening,  but  dryness  of  the  throat  and  thirst  are  often  present. 
Larger  doses  do  not  cause  deeper  sleep  but  give  rise  to  delirium  and 
excitement  resembling  those  following  atropine. 

In  one  or  two  cases  collapse  has  been  observed  after  scopolamine. 
The  vaso-motor  and  respiratory  centres  do  not  seem  to  be  stimulated 
as  by  atropine,  the  blood-pressure  falling  and  the  respiration  generally 
becoming  slower  from  the  beginning. 

In  the  lower  mammals  scopolamine  reduces  the  excitability  of  the 
motor  areas  as  tested  by  electric  shocks,  while  the  reflex  excitability  in 

19 


290  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

the  frog  is  not  increased  as  by  atropine.  Hyoscine  appears  to  be 
excreted  or  destroyed  in  the  tissues  much  more  rapidly  than  atropine, 
for  its  effects  last  a  shorter  time. 

JThe  action  of  hyoscine,  then,  seems  to  correspond  with  that  of  atro-  1 
pine,  save  that  the  central  nervous  system  is  here  depressed,  while  the  i 
action  on  the  peripheral  nerve  ends  is  stronger.      It  depresses  the  brain    » 
in  very  smairquantities,  J  mg.  (T£¥  gr.)  being  generally  sufficient  to 
cause  sleep.     It  does  not  seem  to  be  so  dangerous  as  the  others  of  the 
series,  for  a  dose  of  5  mgs.  (^  gr.)  has  been  recovered  from  in  man, 
and  over  half  a  gramme  (7J-  grs.)  administered  to  a  small  cat  did  not 
kill    the   animal.     A    certain    degree  of   tolerance    is    produced  after 
repeated  use,  so  that  the  dose  has  to  be  increased  after  a  week  or  two. 

It  must  be  remarked  that  the  action  of  hyoscine  as  a  hypnotic  differs 
considerably  from  that  of  opium  and  of  the  members Tot  tne  methane 
series ;  it  is  very  much  less  reliable,  and  the  sleep  produced  resembles 
much  more  nearly  natural  sleep.  This  difference  has  not  been  explained, 
but  it  seems  probable  that  the  seat  of  action  differs  in  all  three. 

The  Other  Natural  Alkaloids  have  been  less  carefully  examined  than 
the  three  foregoing ;  such  mixtures  as  duboisine  of  course  combine  the 
effects  of  their  constituents.  The  pseudo-hyoscyamine  of  Merck  seems 
to  be  very  feebly  active,  causing  dilatation  of  the  pupil  on  local  appli- 
cation, but  having  little  or  no  effect  when  given  internally. 

Among  the  Artificial  Tropeines,  only  one  has  received  much  attention 
at  the  hands  of  either  experimental    or  practical  therapeutists.     This 
is    Homatropine,  a  compound    of    tropine    and   mandelic   acid,  which 
is  found  to  be  less  poisonous  than  atropine  but  to  resemble  it  in  the 
symptoms  produced  by  an  overdose.     The  mydriatic  effects  pass  off 
much  sooner  than  those  produced  by  the  usual  solutions  of  atropine, 
and  are  said  to  appear  more  rapidly  and  to  be  less  complete.     It  was 
formerly  supposed  that  homatropine  caused  no  increase  in  the  intra- 
ocular tension,  but  this  has  been  shown  to  be  erroneous,  although  it  is 
less  active  in  this  direction  than  atropine. 

Several  other  tropeines  have  been  examined  by  Falck  and  Gottlieb,  who 
found  that  they  varied  a  great  deal  in  their  action  on  the  lower  animals. 
Many  of  them  produce  no  paralysis  of  the  oculomotor  or  the  vagus  termi- 
nations, while  others  act  here  in  the  same  way  as  atropine,  but  differ  from 
it  in  power.  It  may  be  stated  that  in  general  the  compounds  of  tropine  with 
the  acids  of  the  methane  series  possess  much  less  of  the  peripheral  atropine 
action  than  the  others.  It  was  formerly  believed  that  even  the  compounds 
with  the  aromatic  acids  were  devoid  of  this  action  unless  the  acid  possessed 
a  hydroxyl  group,  but  this  general  statement  has  been  shown  to  be  erro- 
neous by  Gottlieb's  work.  A  considerable  variation  also  exists  in  the  effects 
of  the  tropeines  on  the  central  nervous  system,  some  causing  excitement  like 
atropine,  while  others  act  as  depressants  and  therefore  resemble  hyoscine. 

As  has  been  mentioned,  many  of  the  tropeines  cause  no  paralysis  of  the 
vagus  inhibitory  terminations  but  they  often  act  as  stimulants  to  the  frog's 
heart.  Tropine  itself  is  a  weakly  toxic,  basic  substance,  which  in  large 
quantities  possesses  this  cardiac  action,  but  does  not  paralyze  the  vagus  nor 
the  oculomotor  terminations  on  local  application.  After  the  injection  of 
large  quantities,  dilatation  of  the  pupil  has  been  observed,  it  is  true,  but  this 
does  not  seem  to  be  of  the  same  origin  as  that  produced  by  atropine. 


ATROPINE  SERIES.  291 

Some  artificial  scopoleines  have  been  examined  recently  by  Schiller,  who 
found  that  they  differed  from  scopolamine  in  being  devoid  of  action  on  the 
nerve  ends  in  the  pupil  and  heart  and  on  the  salivary  secretion.  They  possess 
a  certain  stimulant  effect  on  the  heart  muscle  like  some  of  the  artificial  tropeines, 
and  all  produce  more  or  less  depression  of  the  central  nervous  system  and  narcosis. 

METHYLATROPINE  (Eumydrin)  is  said  to  possess  the  peripheral  action  of  atro- 
pine  without  its  effects  on  the  central  nervous  system.  Its  effects  on  the  pupil 
in  1  per  cent,  solution  appear  sooner  and  are  less  lasting  than  those  of  atropine. 

The  action  of  the  Crude  Drugs  is  very  similar  to  that  of  the  active 
principles  already  discussed.  The  peripheral  action  of  all  of  them  is 
v  therefore  almost  identical  in  kind,  though  varying  in  degree.  In  con-  \ 
\sidering  their  effects  on  the  central  nervous  system  it  must  be  remem-  I 
Jbered  that  those  containing  much  atropine  are  more  stimulant,  those  | 
'with  hyoscine  more  sedative.  In  belladonna  preparations  the  quantity 
of  hyoscyamine  varies  a  good  deal,  and  it  is  said  that  no  atropine  is 
present  in  the  fresh  plant,  but  that  during  the  various  processes  of  ex- 
traction some  or  all  of  the  original  hyoscyamine  becomes  changed  to 
atropine ;  the  relative  proportion  of  these  two  poisons  probably  varies 
in  different  preparations,  therefore.  In  hyoscyamus  and  scopola  the 
presence  of  scopolamine  produces  a  much  more  narcotic  effect  than  is 
obtained  from  belladonna,  while  datura  is  generally  said  to  be  less  seda- 
tive than  the  former,  but  less  stimulant  than  the  latter.  Duboisia  also 
seems  rather  sedative  than  stimulant,  but  its  action  and  that  of  its 
so-called  alkaloid  must  vary  considerably,  since  the  latter  consists  at 
one  time  of  hyoscine,  at  another  of  hyoscyamine.  Mandragora  con- 
taining hyoscyamine  and  hyoscine  probably  resembles  hyoscyamus  in 
its  effects. 

PREPARATIONS. 

U.  S.  F. — Belladonnae  Folia,  the  leaves  of  Atropa  Belladonna. 

EXTRACTUM  BELLADONNA  FOLIORUM,  0.005-0.03  G.  (TV~2  gr.)- 

TINCTURA  BELLADONNA  FOLIORUM,  0.3-1  c.c  (5-15  mins.). 

Utiguentum  Belladonnce. 

EMPLASTRUM  BELLADONNA. 

Belladonnas  Radix,  the  root  of  Atropa  Belladonna. 

Fluidextractum  Belladonnce  Radicis,  0.05-0.1  c.c.  (1-2  rnins.). 

LINIMENTUM  BELLADONNA,  containing  camphor. 

Hyoscyamus,  the  leaves  of  Hyoscyamus  niger,  henbane. 

EXTRACTUM  HYOSCYAMI,  0.03-0.2  G.  (£-3grs.), 

Fluidextractum  Hyoscyami,  0.3-1  c.c.  (5-15  mins.). 

TINCTURA  HYOSCYAMI,  1-4  c.c.  (15-60  mins. ). 

STRAMONIUM,  the  dried  leaves  of  Datura  Stramonium. 

Extractum  Stramonii,  0.01  G.  (£  gr.). 

Fluidextractum  Stramonii,  0.5  c.c.  (1  min.). 

Tinctura  Stramonii,  0.5  c.c.  (8  mins.). 

Unguentum  Stramonii. 

SCOPOLA,  the  dried  rhizome  of  Scopola  carniolica. 

Extractum  Scopolce,  0.01  G.  (£  gr.). 

Fluidextractum  Scopolce,  0.05  c.c.  (1  min.). 

B.  P. — Belladonnas  Folia,  the  fresh  leaves  and  branches  of  Atropa  Bella- 
donna. 

Extractum  Belladonnce  Viride,  |— 1  gr. 

Succus  Belladonnce,  5-15  mins. 

Belladonnas  Radix,  the  root  of  Atropa  Belladonna. 

EXTRACTUM  BELLADONNCE  ALCOHOLICUM  (1  per  cent,  of  alkaloids),  ^-1  gr. 


292  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

EXTRACTUM  BELLADONNA  ALCOHOLICUM  (1  per  cent,  of  alkaloids),  £-1  gr. 
Extractum  Belladonna  Liquidum  (f  per  cent,  of  alkaloids),  £-1  min. 
TINCTURA  BELLADONNA  (^  per  cent,  alkaloids),  5-15  mins. 
LINIMENTUM  BELLADONNA. 
Unguentum  Belladonna. 
EMPLASTRUM  BELLADONNA. 

Suppositoria  Belladonnse,  each  containing  -fa  gr-  of  alkaloids. 
Hyoscyami  Folia,  the  fresh  leaves,  flowers  and  branches  of  Hyoscyamus 
niger,  henbane. 

EXTRACTUM  HYOSCYAMI  VIRIDE,  2-8  grs. 
Tinctura  Hyoscyami,  £-1  fl.  dr. 
Succus  Hyoscyami,  £-1  fl.  dr. 

Stramonii  Folia,  the  dried  leaves  of  Datura  Stramonium. 
Tinctura  Stramonii,  5-15  mins. 

Stramonii  Semina,  the  seeds  of  Datura  Stramonium. 
Extractum  Stramonii,  \-\.  gr. 

Alkaloids. 

ATROPINA  (U.  S.  P.,  B.  P.),  an  alkaloid  (C17H2?NO3)  derived  from  bella- 
donna and  forming  white,  acicular  crystals,  very  little  soluble  in  water,  but 
soluble  in  alcohol  and  ether,  and  having  a  bitter  taste.  0.0005-0.001  G., 

J-l  mg.  (-2£o-rio  Sr-  B-  P-)- 

ATROPIN^E  SULPHAS  (U.  S.  P.,  B.  P.),  a  white,  crystalline  powder,  with  a 
very  bitter  taste,  soluble  in  water  and  alcohol.  Dose,  as  for  atropine. 

Oleatum  Atropince  (U.  S.  P.),  2  per  cent. 

Unguentum  Atropince  (B.  P.),  4  per  cent. 

Liquor  Atropince  (B.  P.),  1  per  cent.,  £-1  min. 

Lamellce  Atropince  (B.  P.),  gelatin  discs,  each  containing  ^^  gr.  of  atropine 
sulphate. 

HYOSCYAMINE  is  not  procurable  in  even  approximately  pure  form  and  might 
well  be  dispensed  with,  as  it  offers  no  advantages  over  atropine. 

HyoscyaminoB  Sulphas  (U.  S.  P.,  B.  P.),  ((C17H23NO3)2H2SO4),  the  sulphate 
of  an  alkaloid  derived  from  Hyoscyamus  niger.  A  crystalline,  deliquescent 
powder  with  a  bitter  acrid  taste,  very  soluble  in  water  and  alcohol  0  0005- 
0.001G.,  i-lmg.  (^o-eV.gr.)- 

Hyoscyamince  Hydrobromidum  (U.  S.  P.  ),  the  hydrobromide  of  hyoscyamine, 
resembles  the  sulphate  in  most  points  but  is  not  deliquescent.  Dose,  as  of  the 
sulphate. 

HyosdncB  Hydrobromidum  (U.  S.  P.,  B.  P.),  (Ci;H21NO4HBr,3H2O),  the  hydro- 
bromide  of  hyoscine  or  scopolamine.  It  is  obtained  from  hyoscyamus,  scopola 
and  other  solanacese,  and  forms  colorless,  transparent  crystals  with  an  acrid, 
bitter  taste,  and  is  very  soluble  in  water,  less  so  in  alcohol.  0.0003-0.0005  G. 


bcopolamince  Hydrobromidum  (U.  S.  P.)  is  identical  with  Hyoscine  hydrobro- 
mide. 

HOMATROPIN.E  HYDROBROMIDUM  (U.  S.  P.,  B.  P.),  (C16H21NO3HBr),  the 
hydrobromide  of  an  alkaloid  prepared  from  tropine  by  condensation  with  man- 
delic  (oxytoluic)  acid,  a  white  crystalline  powder  soluble  in  6  parts  of  cold  water. 

Lamellce  Homatropince  (B.  P.),  homatropine  discs,  each  weighing  -£$  gr.  and 
containing  T^  gr.  of  homatropine  hydrobromide. 

Therapeutic  Uses.  —  The  numerous  changes  produced  by  atropine  and 
its  congeners  on  the  organism  would  indicate  for  them  a  very  wide 
sphere  of  usefulness  were  it  possible  to  elicit  their  action  on  one  organ 
without  affecting  others  and  this  difficulty  may  perhaps  be  overcome 
in  the  future,  when  the  different  individuals  of  the  series  have  been 
more  carefully  compared,  and  new  tropeines  and  other  modifications 
of  the  tropine  radicle  are  available  in  therapeutics. 


ATROPINE  SERIES.  293 

The  peripheral  action  of  the  whole  series,  as  far  as  it  is  at  present 
known,  is  so  uniform  that  any  member  might  be  used  to  elicit  it, 
but  the  only  one  that  has  come  into  general  use  for  its  peripheral 
effects  is  atropine.  The  purposes  for  which  atropine  is  employed  may 
be  divided  into  groups  as  follows  : 

To  Arrest  or  Lessen  Secretions.  —  In  rare  cases  of  excessive  salivation 
atropine  has  proved  of  service,  but  it  is  much  more  frequently  used  to 
lessen  the  joersgiration,  especially  in  the  later  stages  of  phthisis.  For 
this  purpose  comparatively  small  quantities,  such  as  J  mg.  (%^-Q  gr.) 
given  by  the  mouth  or  hypodermically  are  generally  sufficient,  or  the 
extract  or  tincture  of  belladonna  may  be  used  instead.  In  local 
sweating,  it  is  often  applied  locally  in  the  form  of  an  ointment,  lini- 
ment, or  plaster,  although  Tappeiner  has  found  that  it  has  no  effect 
when  thus  employed.  Atropine  is  also  used  to  arrest  the  secretion  of 
the  milk,  for  although  it  has  not  the  immediate  effects  on  the  mammary 
that  it  possesses  on  the  salivary  glands,  the  secretion  is  diminished  and 
eventually  ceases  under  its  influence,  which  prevents  the  gland  receiv- 
ing any  stimulation  from  the  central  nervous  system.  Belladonna  is 
usually  applied  locally  for  this  purpose  in  the  form  of  the  plaster,  or 
less  commonly  as  the  ointment  or  liniment. 

To  Paralyze  the  Cardiac  Inhibitory  Terminations.  —  For  this  purpose 
a  slightly  larger  quantity  is  required  than  is  necessary  to  stop  the  secre- 
tions, and  the  administration  of  sufficient  atropine  to  paralyze  the  vagus 
(1  mg.)  therefore  involves  unpleasant  dryness  of  the  throat  and  diffi- 
culty in  swallowing.  In  cases  where  slowing  of  the  heart  tends  to  be 
dangerous  in  itself,  more  especially  in  poisoning  with  certain  substances 
to  be  discussed  later,  atropine  is  indicated.  It  may  also  be  used  for 
diagnostic  purposes,  to  find  if  bradycardia  is  due  to  disease  of  the  heart 
muscle  or  to  inhibition.  It  may  be  repeated  here  that  the  resultant 
quickening  is  much  less  in  old  than  in  middle-aged  people,  and  it  is 
said  that  in  many  cases  of  old  valvular  lesion  the  administration  of 
atropine  is  followed  by  little  or  no  acceleration.  Some  forms  of  inter- 
mission of  the  pulse  are  due  to  unusual  activity  of  the  inhibitory  appa- 
ratus, and  these  may  be  remedied  by  atropine ;  but  this  intermission 
possesses  little  importance,  and  seems  to  require  no  therapeutic  treat- 
ment. Atropine  may  be  used  to  diagnose  it  from  the  more  significant 
forms  present  in  organic  disease  of  the  heart.  The  use  of  atropine  to 
>  paralyze  the  vagus  terminations  before  the  administration  of  an  anes- 
thetic has  been  discussed  already.  (See  page  176.) 

\*  To  Paralyze  the  Terminations  of  the  Motor  Nerves  in  the  Iris  and 
f  Ciliary  Muscles. — It  is  used  for  this  purpose  largely  in  ophthalmology 
as  a  means  of  diagnosis  and  of  treatment,  and  the  precise  conditions  in 
which  it  is  indicated  may  be  treated  better  in  text-books  on  this  sub- 
ject than  here.  For  these  objects,  solutions  of  the  alkaloid al  salts  are 
generally  applied  to  the  conjunctiva,  when  enough  of  the  alkaloid  passes 
into  the  eye  by  a  process  of  imbibition  to  produce  marked  local  effects 
without  affecting  more  distant  organs.  In  order  to  dilate  the  pupil, 
extremely  dilute  solutions  are  used  ;  a  few  drops  of  a  solution  of  one  in 


294  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

1,000,  or  even  of  one  in  10,000,  are  quite  sufficient.  Much  stronger 
solutions  are  required  to  paralyze  the  accommodation,  and  as  a  general 
rule  1  per  cent,  is  used.  These  strong  solutions  produce  complete 
paralysis  in  1-1  \  hours,  and  the  accommodation  does  not  recover 
completely  until  after  5-7  days,  while  the  pupil  may  not  regain  its 
normal  size  for  10-14  days.  The  application  of  even  weaker  atropine 
solution  renders  the  sight  imperfect  for  an  inconveniently  long  period, 
and  hyoscine  and  homatropine  are  therefore  much  used  in  its  stead. 
The  symptoms  produced  by  a  1  per  cent,  solution  of  homatropine  pass 
off,  or  at  any  rate  become  very  much  less  marked  in  the  course  of  36 
hours.  These  are  consequently  preferable  for  diagnostic  purposes, 
while  atropine  is  rather  to  be  used  where  it  is  desirable  to  produce  a 
paralysis  of  longer  duration,  as  in  various  inflammatory  conditions  of 
the  iris  or  cornea.  Atropine  is  also  preferable  where  complete  paralysis 
of  the  accommodation  is  necessary,  as  homatropine  often  fails  to  effect 
this.  Atropine  and  its  congeners  are  contraindicated  where  there  is 
any  suspicion  of  glaucoma,  as,  owing  to  their  action  on  the  intraocular 
pressure,  they  may  either  aggravate  the  disease  already  present  or  pre- 
cipitate an  acute  attack.  When  dilatation  of  the  pupil  is  necessary  and 
there  is  reason  to  apprehend  the  results  on  the  intraocular  pressure, 
homatropine  should  be  employed  as  its  effects  can  be  readily  controlled 
by  eserine.  Numerous  cases  of  poisoning  have  arisen  from  the  exten- 
sive use  of  atropine  in  diseased  conditions  of  the  eye.  It  is  often 
asserted  that  it  passes  down  with  the  tears  through  the  lachrymal  duct 
and  is  absorbed  from  the  nose,  throat  and  stomach,  but  as  a  matter  of 
fact  it  may  be  absorbed  from  the  conjunctiva  itself.  The  symptoms 
are  generally  only  the  milder  ones  of  atropine  poisoning — dryness  of 
the  throat  and  slight  excitement — but  dangerous  and  even  fatal  poison- 
ing has  also  arisen  from  its  local  application.  In  many  cases  this  is 
due  to  the  application  of  unnecessarily  strong  solutions  to  the  eye,  but, 
on  the  other  hand,  some  patients  seem  abnormally  sensitive  to  the 
action  of  atropine,  and  hyoscine,  or  better  homatropine,  ought  to  be 
preferred.  In  rare  cases  a  curious  inflammatory  condition  of  the  con- 
junctiva  is  set  up  by  atropine,  and  this  is  often  supposed  to  be  due  to 
the  use  of  irritant  preparations,  but  sometimes  seems  to  follow  the 
application  of  the  absolutely  pure  alkaloid,  and  is  apparently  an  idio- 
syncrasy ;  it  may,  perhaps,  be  explained  by  the  arrest  of  the  ordinary 
secretions  of  the  lachrymal  gland  and  conjunctiva  in  these  cases. 
Sometimes  discs  of  gelatin  impregnated  with  atropine  or  homatropine 
sulphate  (B.  P.)  are  applied  to  the  conjunctiva  instead  of  solutions  of 
the  salts. 

To  Relax  Spasm  of  the  Intestines. — In  various  forms  of  colic  atro- 
pine is  oFvery  great  service  in  lessening  pain  and  allowing  the  passage 
of  the  intestinal  contents ;  for  instance,  it  is  preferable  to  morphine  in 
lead  colic,  as  it  does  not  cause  constipation.  Hernia  and  volvulus  are 
sometimes  reduced  by  atropine  injected  hypodermically  (3  mg.  or  JQ- 
gr.).  It  is  often  prescribed  along  with  purgatives  in  order  to  lessen 
the  griping  which  they  produce,  and  has  been  used  as  a  laxative  in 


ATROPINE  SERIES.  295 

some  forms  of  constipation  with  considerable  success.  For  action  on 
the  bowel  it  is  generally  prescribed  in  pill  form  as  one  of  the  extracts 
of  belladonna  or  hyoscyamus.  The  object  of  prescribing  an  impure 
preparation  instead  of  the  alkaloid  is  to  allow  of  a  strong  local  action 

y  along  the  intestinal  wall  along  with  a  slow  and  imperfect  absorption, 
t-   as  the  pure  alkaloidal  salts  are  liable  to  be  absorbed  in  the  stomach. 
To^Relax  Spasms  of  the  Involuntary  Muscles  of  Other  Organs.  —  In 

Vthe  spasmodic  contraction  of  the  ureters  and  bile  jlucts  due  to  calculi, 
atropine  is  occasionally  prescribed  either  in  the  form  of  a  pill  or  in 
solution  for  internal  use,  or  by  hypodermic  application.  In  some  forms 
of  asthma  due  to  contraction  of  the  bronchial  muscles,  atropine  has 
been  applied  locally  by  means  of  a  spray  or  given  internally,  and 
stramonium  leaves  are  often  found  of  benefit  when  made  up  into  cigar- 
ettes and  inhaled  when  the  attack  comes  on  ;  the  smoke  has  been  shown 
to  contain  small  quantities  of  the  alkaloids.  Some  cases  of  asthma 
are  said  to  have  been  permanently  cured  by  treatment  with  atro- 
pine internally.  An  ointment  of  atropine  has  also  been  applied  to 
the  cervix  uteri  with  the  hope  of  relaxing  spasm  during  labor,  but  the 
results  are  somewhat  questionable.  Perhaps  this  action  in  relaxing 
spasmodic  contractions  of  nervous  origin  may  also  explain  the  beneficial 

.      effects  obtained  in  cases  of  incontinence  of  urine  in  children  in  which 

j     belladonna  has  long  been  the  most  reliable  remedy. 

ToJLessen  Pain. — Belladonna  liniment,  plaster  and  ointment  have 

/^long  enjoyed  a  considerable  reputation  as  local  anodynes,  and  atropine 
has  not  infrequently  been  injected  into  painful  areas.  This  anodyne 
action  is  very  weak  compared  with  that  of  cocaine,  however,  and  the 

/?  preparations  of  atropine  have  been  less  used  of  late  years.     In  some 

i  \  forms  of  gastralgia  atropine  has  also  been  suggested. 

\V     The  Effects  on  the  Central  Nervous  System  of  the  members  of  this 

r  group  are  very  different,  and  the  purposes  for  which  they  are  used  are 
diametrically  opposite.  Atropine  is  used  as  a  stimulant  in  various 
conditions  of  depression  of  the  brain  and  medulla  oblongata.  Thus, 
in  collapse  its  hypodermic  injection  may  be  of  use  to  stimulate  the 
respiratory  and  vaso-constrictor  centres,  and  at  the  same  time  to  free 
tfie  heart  from  excessive  inhibition.  In  dangerous  poisoning  from 
narcotic  and  hypnotic  drugs,  more  especially  in  opium  poisoning, 
atropine  has  been  largely  used.  A  long  and  weary  dispute  as  to  the 
value  of  atropine  in  those  cases  has  been  carried  on,  for  the  history  of 
which  the  reader  is  referred  to  the  recent  paper  by  Bashford.  The 
results  indicate  that  atropine  is  useful  in  morphine  poisoning  through 
stimulating  the  respiratory  centre,  which  is  the  danger  point.  But  it 
must  be  employed  in  small  quantities  (1.5  mg.  or  -fa  gr.),  as  large 
doses,  such  as  have  frequently  been  advised,  tend  to  depress  the  central 
nervous  system  and  thus  to  aid  rather  than  to  antagonize  the  action  of 
morphine  on  the  respiration.  It  may  be  questioned  whether  in  any 
case  atropine  may  not  be  replaced  by  caffeine  with  advantage.  The 
former  stimulates  the  medullary  centres  but  subsequently  paralyzes 
them,  while  caffeine,  even  in  comparatively  large  quantities,  does  not 
seem  to  have  a  depressant  action  in  man. 


296  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Atropine  at  one  time  had  some  reputation  in  the  treatment  of  epi- 
lepsy. It  has  been  shown  both  clinically  and  experimentally  that  this 
reputation  was  undeserved,  the  number  of  attacks  and  their  violence 
being  rather  increased  than  diminished  by  its  exhibition  ;  the  belief  in  its 
powers  arose  from  the  use  of  impure  preparations  containing  hyoscine. 

In  some  spasmodic  diseases,  such  as  whooping-cough,  belladonna 
preparations  have  long  enjoyed  a  wide  reputation ;  a  possible  explana- 
tion is  that  the  hyoscine  may  allay  the  spasms  by  reducing  the  excita- 
bility of  the  respiratory  centre. 

Hyoscine  or  scopolamine  has  been  used  as  a  narcotic  to  depress  the 
central  nervous  system ;  it  is  of  great  efficacy  in  insanity,  producing 
Isound  and  ret resTTmg  sleep,  but  is  of  less  value  in  controlling  the  excite- 
ment during  the  day,  and  may  in  fact  increase  it.  Hyoscine  is  also 
used  with  benefit  in  various  forms  of  tremor  of  central  origin,  and.  is 
said  to  lessen  sexual  excitement.  Its  hypnotic  action  does  not  seem 
to  be  of  'Tn*ig"*same^  "nature  as  that  of  opium,  for  in  sleeplessness  pro- 
duced by  pain  it  is  of  comparatively  little  value,  and  it  has  no  power 
to  relieve  pain  itself.  It  differs  from  chloral  in  not  producing  deep 
sleep,  for  patients  under  the  influence  of  hyoscine  can  always  be  aroused 
and  are  much  less  confused  than  after  choral.  The  special  indications 
ifor  hyoscine  seem  to  be  sleeplessness  due  to  abnormal  activity  of  the 
taotor  areas  and  some  forms  of  tremor. 

Comparatively  recently  morphine  and  hyoscine  have  been  injected 
as  a  preliminary  to  surgical  operations,  but  as  a  general  rule  the  nar- 
cosis induced  is  insufficient.  As  a  preliminary  to  the  use  of  ether  the 
procedure  seems  to  be  of  value,  as  much  less  of  the  anaesthetic  is  re- 
quired ;  10  mgs.  (J  gr.)  of  morphine  and  0.3  mg.  (^^  gr.)  of  hyoscine 
are  injected  two  hours  before  the  operation. 

Poisoning.  —  In  cases  of  poisoning  with  belladonna  and  its  allies  the 
treatment  is  purely  symptomatic.  In  the  excitement  stage  sedatives 
may  be  used  ;  perhaps  chloroform  and  ether  are  best,  as  their  effects 
are  more  transient  than  the  others.  Morphine  has  been  advised,  but 
its  action  on  the  respiratory  centre  renders  its  use  dangerous,  as  in 
severe  atropine  poisoning  the  stimulation  soon  passes  into  depression, 
and  the  effects  of  the  poison  and  its  so-called  antidote  therefore  sup- 
plement each  other.  Chloroform  and  ether,  on  the  other  hand,  may 
be  used  to  control  the  spasms  and  then  stopped  when  these  pass  off. 
In  the  depression  stage  caffeine  may  be  used,  and  eventually  artificial 
respiration.  Pilocarpine  is  of  course  useless,  as  it  does  not  antagonize 
atropine  in  the  brain,  which  is  the  point  of  danger. 

BIBLIOGRAPHY. 

Bezold  u.  Bloebaum.     Untersuch.  a.  d.  physiol.  Laborator.  zu  Wiirzburg,  i.,  p.  1. 

Heidenhain.     Pfl  tiger's  Archiv,  v.,  p.  309,  and  ix.,  p.  335. 

.Luchsinger.     Ibid.,  xv.,  p.  482  ;  xviii.,  p.  587,  and  xxvi.,  p.  459. 

Albertoni.     Arch.  f.  exp.  Path.  u.  Pharm.,  xv.,  p.  258. 

Hammerbacher.     Pfliiger's  Arch.,  xxxiii.,  p.  228. 

Mironow.     Arch,  de  Scienc.  biologique,  iii.,  p.  353. 

Binz.     Centralbl.  f.  klin.  Med.,  1893,  p.  25. 

Ott.     Therap.  Gaz.,  1887,  p.  511. 

Alms.     Arch.  f.  Anat.  u.  Phys.,  1888,  p.  416. 


ATROPINE  SERIES.  297 

Bayliss  and  Starling.     Journ.  of  Physiol.,  xxiv.,  p.  99. 
Dixon.     Ibid.,  xxviii.,  p.  57. 
Magnus.     Ergebnisse  der  Physiol.,  ii.  (2),  p.  653. 
Riegel.     Ztschr.  f.  klin.  Med.,  xxxvii.,  p.  381. 
Schiff.     Arch.  f.  Verdauungskrankh.,  vi.,  p.  107. 
Gottlieb.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii.,  p.  218. 
Cushny.     Journ.  of  Physiology,  xxx.,  p.  176,  xxxii.,  p.  501. 
Bashford.     Arch,  internal,  de  Pharmacodyn.,  viii.,  p.  311. 
Vollmer.    Arch.  f.  exp.  Path.  u.  Pharm.,  xxx.,  p.  385. 
Levison.     Berl.  klin.  Woch.,  1894,  p.  891. 
Orlowski.     Diss.,  Dorpat,  1891. 
Mutter.     Diss.,  Dorpat,  1891. 
Mathews.     Am.  Journ.  of  Physiol.,  iv.,  p.  482. 

Kochmann.     Arch,  internal,  de  Pharmacodyn.,  xii.,  p.  109.     (Hyoscine.) 
Schiller.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxviu.,  p.  71. 
Anrep.     Pfliiger's  Archiv,  xxi.,  p.  78. 
Schultz.     Arch.  f.  Anat.  u.  Phys.,  1898,  p.  53. 
Thompson.     Ibid.,  1894,  p.  117. 

Walti.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvi.,  p.  411. 

Strieker  u.  Spina.     Wiener  Sitzungsber.,  Math.-nat.  Classe,  Ixxx.,  Abt.  iii.,  p.  117. 
Spiro.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxviii.,  p.  113. 
Wiechowski.     Ibid.,  xlvi.,  p.  154. 
Hedbom.     Skandin.  Arch.  f.  Phys.,  viii.,  p.  171. 

Compare  also  the  Literature  of  pilocarpine  and  muscarine,  nicotine  and  physostig- 
nrine. 

Agaricin.1 

White  Agaric  (Agaricus  albus,  Boletus  Laricis),  a  fungus  growing 
on  the  European  larch  tree,  was  formerly  a  purgative  and  antihydrotic 
of  some  repute.  Its  use  to  lessen  the  perspiration  (antihydrotic)  has 
been  revived  of  late  years,  or  rather  a  preparation  known  as  agaricin 
and  containing  the  active  principle  has  been  introduced  into  thera- 
peutics. Agaric  or  Agaricinic  acid,  the  active  constituent,  belongs  to 
the  malic  acid  series  and  has  the  formula  C14H27(OH)(COOH)2. 

Action. — Both  the  acid  and  its  sodium  salt  irritate  the  mucous  membranes 
and  wounded  surfaces,  and  cause  inflammation  and  even  suppuration  when 
injected  subcutaneously.  Large  quantities  irritate  the  stomach  and  intestine 
and  cause  vomiting  and  purging,  but  these  are  more  liable  to  arise  from  the 
impure  agaricin  owing  to  its  containing  resinous  acids.  Injected  into  the 
frog,  agaric  acid  paralyzes  the  central  nervous  system,  weakens  the  heart 
and  stops  the  secretion  of  the  skin  glands.  In  mammals  the  intravenous 
injection  of  agaric  acid  is  followed  by  depression,  weakness,  dyspnoea. and 
death.  The  medulla  oblongata  is  first  stimulated  and  then  paralyzed,  as  is 
shown  by  the  blood-pressure  first  rising  and  then  falling  to  zero,  while  the 
heart  is  primarily  slowed  by  inhibitory  action  and  later  regains  its  rhythm, 
to  eventually  fail  after  the  arrest  of  the  breathing.  Animals  can  only  be 
poisoned  with  difficulty  by  the  subcutaneous  injection  of  agaricin,  and  no 
general  symptoms  are  elicited  when  it  is  administered  by  the  mouth. 

The  most  interesting  feature  of  the  action  of  agaric  salts  is  the  arrest 
of  the  sweat  secretion,  which  is  caused  by  peripheral  action,  for  stimu- 
lation of  the  nerves  of  the  cat's  foot  fails  to  elicit  perspiration  after  its 
ingestion.  It  thus  acts  on  the  same  peripheral  mechanism  as  atropine 
in  all  probability,  that  is,  on  the  terminations  of  the  secretory  nerves, 
but  differs  from  atropine  in  acting  only  in  the  sweat  glands,  for  the 

1  Agaricin  does  not  resemble  atropine  in  its  general  action,  nor  in  its  chemical  prop- 
erties, but  it  may  be  inserted  at  this  point  until  these  are  more  fully  elucidated. 


298  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

saliva,  tears  and  other  secretions  are  not  hindered  by  it,  and  may,  in 
fact,  be  increased  by  its  causing  nausea.  It  is  also  devoid  of  action 
on  the  nerve  terminations  in  the  heart  and  pupil.  Atropine  acts  much 
more  powerfully  than  agaric  acid,  at  least  twenty  times  as  much  of  the 
latter  being  required  to  arrest  the  sweat  secretion. 

Uses. — Agaricin  is  used  in  the  night  sweats  of  phthisis  and  other 
similar  conditions  and  is  generally  given  in  pill  form  in  doses  of  5-60 
mgs.  (^-l  gr-)«  The  commercial  agaricin  often  contains  a  large  per- 
centage of  impurities  and  has  to  be  given  in  larger  quantities,  but  the 
treatment  ought  to  be  begun  with  small  doses.  Tolerance  is  said  to  be 
acquired  after  some  time,  and  the  dose  has  then  to  be  increased.  The 
best  results  are  got  when  the  pills  are  taken  5-6  hours  before  retiring, 
as  the  acid  is  only  slowly  absorbed.  If  agaricin  causes  intestinal 
irritation  and  diarrhoaa  it  may  be  given  with  opium,  but  as  in  phthisis 
all  irritation  of  the  bowel  is  to  be  avoided,  the  remedy  ought  perhaps 
to  be  stopped  when  any  such  disturbance  arises. 

Other  antihydrotics  are  atropine  and  camphoric  acid.  Agaricin  is 
preferable  to  atropine,  because  the  latter  tends  to  cause  dry  ness  of  the 
throat  and  other  symptoms  when  it  is  given  for  some  time  even  in 
very  small  doses. 

BlBLIOGEAPHY. 


Hofmeister.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxv.,  p.  189. 


XIII.     COCAINE, 

Cocaine  is  a  comparatively  recent  addition  to  therapeutics,  although 
the  coca  plant  has  been  in  use  in  South  America  for  centuries.  It  is 
indigenous  there,  but  has  been  introduced  into  India,  Ceylon  and  Java. 
The  leaves  of  the  coca  grown  in  Peru  and  Bolivia  contain  cocaine 
along  with  small  quantities  of  other  alkaloids,  but  the  India  coca  and 
still  more  the  Java  leaves  contain  a  smaller  proportion  of  cocaine  and 
a  larger  amount  of  the  less  known  alkaloids. 

Cocaine,  like  atropine,  is  readily  decomposed  into  several  constitu- 
ents. On  heating  it  with  water,  methyl  alcohol  is  thrown  off',  leaving 
Benzoyl-ecgonine,  which  may  be  further  broken  up  into  benzoic  acid 
and  Ecgonine,  a  pyridine  derivative. 

Ecgonine.  Cocaine. 

CH  — CH CH'COOH 


N(CHJCH'OH  N(CH)C 

L    '  .  L    1_      'I 


2—  CH  2 


Cocaine  is  capable  of  being  changed  in  several  different  parts  of  its  struc- 
ture. Thus  ethyl  or  propyl  may  be  substituted  for  the  methyl  group,  the 
benzoyl  radicle  may  be  replaced  by  various  others,  such  as  cinnamyl,  and  so 
on.  Many  artificial  cocaines  have  been  formed  in  this  way,  and  several  of 
these  have  since  been  found  in  the  cultivated  plant,  as  for  example  Cinna- 
myl-cocaine,  in  which  cinnamyl  occupies  the  position  of  benzoyl  in  the  above 
formula  Various  other  alkaloids,  such  as  Cocamine,  Isococamine,  Homococa- 


COCAINE.  299 

mine  and  Homoisococamine  are  also  present ;  all  of  these  contain  the  ecgonine 
molecule  in  combination  with  various  acids,  and  cocaine  may  be  formed  from 
all  of  them  by  isolating  the  ecgonine  and  combining  it  with  benzoic  acid  and 
methyl.  These  alkaloids  are  present  in  the  plant  in  very  small  quantities 
compared  with  cocaine  and  have  not  been  used  therapeutically.1  Another 
alkaloid  which  has  been  found  in  the  Java  coca  is  Tropacocaine,  which  is  a 
combination  of  benzoic  acid  and  a  base  (C8Hi5NO)  which  was  formerly  sup- 
posed to  be  identical  with  the  pseudotropine  derived  from  hyoscine,  but  has 
been  shown  to  be  of  different  constitution.  It  will  be  observed  that  the 
formula  of  ecgonine  resembles  very  closely  that  of  tropine,  each  containing 
the  same  nucleus,  but  differing  slightly  in  the  radicles  attached  to  it. 

The  most  important  effects  of  cocaine  are  those  on  the  central  nerv- 
ous system  and  on  the  sensory  nerves. 

Symptoms. — The  symptoms  of  cocaine  poisoning  in  man  vary  a  good 
deal  in  different  individuals.  In  most  cases  small  quantities  produce 
some  excitement,  pleasurable  or  disagreeable.  The  patient  is  gener- 
ally restless  and  more  garrulous  than  in  ordinary  life,  often  somewhat 
anxious  and  confused.  But  very  often  a  small  dose  is  followed  by  a 
calm,  languorous  state,  somewhat  resembling  that  induced  by  small 
quantities  of  morphine,  but  differing  from  it  in  there  being  less  tend- 
ency to  sleep.  The  pulse  is  accelerated,  the  respiration  is  quick  and 
deep,  the  pupil  generally  dilated,  and  headache  and  dryness  of  the 
throat  are  often  complained  of.  The  reflexes  may  be  found  somewhat 
more  easily  excited  than  usual  and  tremors  or  slight  convulsive  move- 
ments often  occur.  Later,  powerful  tonic  or  clonic  convulsions  super- 
vene, the  heart  becomes  extremely  accelerated,  the  breathing  becomes 
rapid  and  dyspnoeic  and  may  be  finally  arrested  during  a  convulsion. 
In  other  cases  the  convulsive  seizures  are  almost  entirely  absent  and 
fainting  and  collapse  occur.  The  skin  is  cyanotic  and  cold,  the  heart 
slow  and  weak ;  the  respiration  is  very  much  depressed  and  death  fol- 
lows from  its  gradual  cessation.  Vomiting  is  occasionally  seen  at  an 
early  stage,  but  is  not  by  any  means  common. 

In  the  dog,  cat  and  rabbit  the  symptoms  are  invariably  those  of 
stimulation  of  the  central  nervous  system.  Soon  after  the  injection, 
the  animal  shows  symptoms  of  great  restlessness  and  excitement ;  it 
seems  unable  to  keep  still,  the  dog  at  first  showing  all  the  signs  of 
affection  and  excitement  which  he  displays  on  ordinary  occasions  on 
being  unchained  or  taken  for  a  walk,  but  afterwards  running  continu- 
ally in  a  circle  and  paying  but  little  heed  to  anything  around  him. 
Still  later  regular  convulsions  occur,  and  these  are  at  first  clonic  but 
may  afterwards  become  tonic,  and  then  resemble  those  seen  in  strych- 
nine poisoning.  Even  before  the  convulsions  appear  the  animal  seems 
partially  unconscious,  and  in  the  intervals  between  them  he  lies  in  an 
apathetic  state,  which  soon  deepens  to  coma  and  death  from  asphyxia. 

In  the  frog  a  certain  amount  of  stimulation  of  the  central  nervous 
system  is  often  displayed  after  small  doses — increased  movement,  exag- 
gerated reflex  and  occasionally  convulsions  —  but  these  soon  pass  into 

1  Hygrine,  which  was  formerly  supposed  to  be  present  in  coca  leaves,  has  been  shown 
not  to  exist  in  them. 


300  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

depression  and  eventually  total  paralysis  of  the  central  nervous  system, 
while  the  peripheral  nerves  still  maintain  their  functions. 

General  Action.  —  Many  of  these  symptoms  point  to  a  stimulant 
action  on  the  Central  Nervous  System,  resembling  closely  that  seen  in 
atropine  poisoning.  Thus  the  garrulity  which  is  so  often  produced  by 
cocaine,  indicates  an  increased  activity  of  the  cerebrum,  and  the  in- 
creased movement  in  the  lower  animals  distinctly  points  to  an  affection 
of  this  part  of  the  brain,  for  the  movements  are  perfectly  coordinated, 
and,  in  fact,  in  the  early  stages  resemble  exactly  those  performed  by 
the  normal  animal  in  a  condition  of  excitement.  Further  evidence  of 
the  action  of  cocaine  on  the  cerebrum  is  offered  by  its  effects  on  mus- 
cular work.  The  natives  of  Peru  and  Bolivia  have  used  it  for  cen- 
turies to  increase  their  endurance  of  fatigue.  The  bearers  of  the 
Andes,  for  example,  march  for  hours  and  days  with  very  little  rest  or 
food  when  they  are  supplied  with  coca  leaves  to  chew.  The  effects  of 
cocaine  on  the  muscular  power  and  on  fatigue  have  been  investigated 
also  by  means  of  the  ergograph  and  dynamometer,  and  all  observers 
are  at  one  in  asserting  that  much  more  work  can  be  done  after  cocaine 
than  before  it,  and  that  it  has  a  surprising  potency  in  removing  fatigue. 
As  regards  mental  work,  its  effects  are  less  known,  but  on  the  analogy 
of  caffeine  it  may  be  supposed  to  increase  the  mental  powers  also  when 
taken  in  small  quantities.  Some  travellers  in  South  America  relate 
marvellous  tales  of  its  producing  feelings  of  the  highest  bliss  and 
power,  but  these  have  not  been  confirmed  by  experience  in  the  action 
of  cocaine  in  less  romantic  regions  of  the  globe.  Cocaine  in  small 
quantities,  then,  increases  the  higher  functions  of  the  cerebrum,  while 
in  somewhat  larger  doses  the  stimulant  effect  spreads  to  the  lower  areas 
and  produces  a  very  great  increase  in  movement,  accompanied,  it  would 
seem,  by  a  depression  of  the  consciousness.  At  the  same  time,  the 
coordinating  or  balancing  powers  seem  affected,  so  that  the  animal 
generally  moves  in  a  circle,  the  symptoms  resembling  the  forced  move- 
ments often  seen  in  affections  of  the  cerebellum. 

The  motor  areas  of  the  cerebrum  have  been  found  to  be  more  easily 
stimulated  by  the  electric  shock  when  cocaine  is  injected,  though  when 
it  is  painted  on  the  surface  of  the  brain  it  lowers  the  irritability,  owing  to 
its  action  as  a  general  protoplasm  poison.  Still  larger  quantities  induce 
convulsions,  which  are  not  of  spinal  origin,  but  point  rather  to  action 
on  some  undetermined  part  of  the  hind  brain.  At  an  early  stage  the 
medulla  oblongata  is  affected,  as  is  shown  by  the  quickened  respiration, 
and  the  exaggerated  reflexes  indicate  stimulation  of  the  spinal  cord, 
which  may  be  so  great  after  very  large  doses  as  to  cause  convulsions 
like  those  produced  by  strychnine.  The  action  of  cocaine  on  the  cen- 
tral nervous  system  is  primarily  a  descending  stimulation,  the  cere- 
brum being  first  affected,  then  the  hind  brain  and  medulla  oblongata, 
and  last  of  all  the  spinal  cord.  Perhaps  it  might  be  better  expressed 
by  saying  that  after  small  quantities  the  chief  symptoms  arise  from 
the  cerebrum,  but  as  the  dose  is  increased  those  from  the  lower  parts  I 
of  the  central  axis  tend  to  become  more  prominent.  After  the  stimu-  J 


COCAINE.  301 

lation  there  succeeds  depression,  which  follows  the  stimulation  down- 
wards, affecting  first  the  cerebrum  and  then  the  lower  divisions.  The 
two  stages  are  not  definitely  divided,  however,  one  part  of  the  cere- 
brum often  showing  distinct  depression,  while  another  is  still  in  a  con- 
dition of  excessive  activity.  In  some  cases,  especially  in  man,  the 
stage  of  excitement  may  be  very  short  or  apparently  absent,  and  the 
whole  course  of  the  symptoms  then  points  to  medullary  depression. 

The  Respiration  after  cocaine  is  much  accelerated  owing  to  central 
stimulation.  At  first  the  depth  of  the  movement  is  not  changed,  but 
as  the  acceleration  progresses,  the  air  inspired  with  eaeh  breath  gradu- 
ally becomes  less.  During  the  convulsions  the  respiration  is  irregular 
or  ceases,  but  it  recovers  again  in  the  intervals,  until  after  a  very  vio- 
lent paroxysm  it  fails  to  be  reinstated.  In  other  cases  the  breathing 
becomes  slower  and  weaker  after  a  time,  and  eventually  stops  from 
paralysis  of  the  centre.  Periodic  respiration  is  frequently  seen,  of  the 
form  generally  known  as  Cheyne-Stokes'.  (See  Morphine,  p.  213.) 

The  Circulation  is  altered  by  cocaine  owing  to  its  action  on  the 
heart  and  on  the  vessels.     The  heart  is  much  accelerated  in  mammals, 
while  in  the  amphibians  this  is  less  often  observed.     The  quickening 
has  been  ascribed  to  paralysis  of  the  inhibitory  terminations,  but  this 
seems  not  to  be  the  case,  for  stimulation  of  the  vagus  slows  the  heart 
;  even  late  in  the  poisoning.     The  heart  is  accelerated,  then,  either  by  ^ 
J  direct  action  of  the  muscle  or  by  stimulation  of  the  accelerator  mech-  { 
£  anism.     It  is  often  slow  before  death,  but  apparently  not  invariably/ 
and  this  is  probably  due  to  direct  action  on  the  muscle.     In  the  frog's 
heart  the  inhibitory  apparatus  is  paralyzed,  the  ganglia  being  affected 
in  the  same  way  as  by  coniine  and  other  drugs. 

The  vessels  are  much  contracted  in  the  earlier  stages  of  poisoning, 
and  this,  together  with  the  increased  rate  of  the  heart,  leads  to  a  very 
considerable  rise  in  the  blood-pressure.     The  constriction  of  the  vessels 
seems  partly  due  to  stimulation  of  the  vaso-constrictor  centre,  for  sec- 
tion of  the  splanchnic  nerves  leads  to  an  immediate  fall  in  the  arterial 
tension.     But  cocaine  also  exercises  a  direct  action  on  the  vessel  walls,  » 
N  for    its    local    application    leads    to    constriction    of    the    vessels    and  C 
wblanching  of  the   mucous   membranes.     It  has  not  been  determined^} 
as  yet  how  far  this  direct  action  on  the  vessel  walls  affects  the  blood- 
pressure  when  cocaine  is  absorbed  or  when  it  is  injected  intraven- 
ously.    The  blood-pressure  subsequently  falls,  apparently  from  periph- 
eral action,  if  Anrep's  assertion  that  stimulation  of  the  splanchnic 
then  produces  no  further  rise  of  pressure  be  correct. 

The  effects  on  the  peripheral  Nerves  and  Muscles  are  disputed,  for 
Mosso  states  that  small  quantities  increase  the  strength  of  the  muscular 
contractions  on  electrical  stimulation  both  in  man  and  animals,  while 
others  have  failed  to  obtain  any  such  effect. 

After  the  injection  of  cocaine,  Anrep  observed  marked  pallor  of  the 
Intestine  and  powerful  peristalsis,  while  very  large  doses  caused  dila- 
tation of  the  mesenteric  vessels  and  lessened  the  movements  of  the 
bowel  probably  through  paralyzing  the  local  nervous  mechanism. 


302  ORGANIC  DR  UGS  A  CTING  A  FTER  ABSORPTION. 

The  Urine  is  sometimes  said  to  be  increased  by  cocaine,  while  in 
other  instances  its  injection  has  been  followed  by  total  anuria  lasting 
for  several  hours.  This  suggests  that  the  action  is  not  a  direct  one  on 
the  kidney,  but  is  caused  merely  through  the  changes  in  the  calibre  of 
the  vessels. 

The  other  Secretions  seem  rather  decreased  than  augmented,  but  no 
very  marked  effects  are  produced  on  them. 

The  Temperature  generally  rises  in  cases  of  poisoning,  sometimes  as 
much  as  3-5°  C.,  from  increased  heat  formation  caused  by  cerebral  action. 
Langlois  and  Richet  observed  that  the  higher  the  temperature  of  the 
animal  the  more  easily  were  convulsions  produced  by  cocaine  and  the 
more  severe  their  type. 

It  used  to  be  supposed  that  cocaine  retarded  the  Tissue  Change  and 
that  less  food  was  required  when  it  was  supplied.  This  was  based  on  the 
statement  of  the  endurance  of  the  natives  of  South  America  when  they  were 
allowed  to  chew  coca  leaves,  and  on  the  discovery  that  the  leaves  also  allay 
hunger  to  some  degree.  But  the  increase  in  the  working  power  is  due  to 
the  effects  on  the  central  nervous  system,  while  the  craving  for  food  is  prob- 
ably lessened  owing  to  the  cocaine  inducing  numbness  of  the  sensory  nerves 
of  the  stomach  through  its  local  action. 

A  curious  effect  of  cocaine,  noted  by  Ehrlich  in  mice,  is  a  widespread 
destruction  of  the  hepatic  cells,  which  become  vacuolated  and  often 
necrosed.  The  liver  is  much  increased  in  size  and  looks  pale  from  fatty 
infiltration,  which  is  also  present,  but  which  is  not  so  characteristic  as  the 
vacuoles. 

Some  cocaine  is  Excreted  by  the  kidney  in  the  dog  when  it  is  ab- 
sorbed into  the  blood,  but  95  per  cent,  of  that  ingested  is  destroyed  in 
the  tissues,  and  this  is  the  fate  of  all  of  it  in  the  rabbit,  in  which  this 
oxidation  proceeds  very  rapidly.     It  is  unknown  whether  it  is  oxidized 
in  man,  who  is  much  more  susceptible  to  its  action  than  these  animals. 
Local  Action.  —  Cocaine  applied  locally  in  most  parts  of  the  body 
^  produces  a  loss  of  sensation  through  its  paralyzing  the  Terminations  of 
-  some  of  the  Sensory  Nerves,  particularly  those  conveying  impressions 
vjpf  pain  and  touch.     It  is  often  stated  that  the  end  organs  of  the  nerves 
concerned  with  the  feeling  of  heat  and  cold  are  also  disorganized,  but 
the  exact  researches  of  Kiesow  show  that  this  is  incorrect,  and  that 
heat  and  cold  are  recognized  as  readily  as  in  the  unaffected  parts  of  the 
body.     Cocaine  applied  to  the  tongue  removes  the  taste  of  bitter  sub- 
stances, while  sweet  and  acid  fluids  lose  their  taste  only  partially,  and 
salt  is  recognized  as  easily  as  usual.1      A  solution  applied  to  the  nasal . 
mucous  membrane  paralyzes  the  sense  of  smell  entirely.    The  anaesthesia 
or  insensibility  to  pain  and  touch  may  be  induced  in  any  of  the  mucous 
membranes  that  can  be  reached  by  cocaine  in  sufficient  concentration, 
pharynx,  larynx,  resophagus,   stomach,   nose,  eye,  urethra,  bladder, 

1 A  curious  contrast  is  presented  in  this  respect  by  gymnemic  acid,  which  is  obtained 
from  the  Gymnema  silvestre,  and  which  removes  the  sensation  of  sweetness,  while 
"bitter"  is  less  affected  and  "acid"  and  "salt"  are  recognized  as  readily  as  usual. 
Gymnemic  acid  does  not  affect  any  other  sense  organs,  as  far  as  is  known,  and  is,  in 
fact,  devoid  of  interest,  except  as  regards  its  effect  on  taste. 


COCAINE.  303 

vagina  and  rectum.  Applied  to  the  unbroken  skin  its  effects  are  less 
marked,  as  it  penetrates  but  slowly  through .  the  horny  epidermis  ;  but 
when  the  epidermis  is  removed  by  abrasions  or  by  skin  disease,  the 
cutaneous  organs  of  sensation  are  acted  on  in  the  same  way  as  those  of 
the  mucous  membranes.  The  deeper  sensory  terminations  can  also  be 
acted  on  by  hypodermic  injection,  which  causes  a  feeling  of  numbness 
and  the  relief  of  pain  in  the  part.  Hypodermic  injection  reaches  not 
only  the  nerve  terminations  of  the  subcutaneous  tissues,  but  also  the 
finer  nerve  bundles,  and  these  too  are  rendered  insensible  as  far  as  the 
solution  extends  to  them.  The  part  may  therefore  be  cut  into  or  be 
subjected  to  other  surgical  treatment  without  pain,  as  long  as  the  knife 
does  not  pass  beyond  the  area  to  which  the  drug  has  penetrated,  and 
numbers  of  grave  surgical  operations  have  been  performed  under  the 
local  anaesthesia  produced  by  cocaine.  Injected  into  the  neighborhood 
of  a  nerve  trunk,  cocaine  penetrates  into  the  fibres  and  induces  anaes- 
thesia of  the  organs  supplied  by  the  nerve,  and  injected  into  the  spinal 
canal,  causes  anaesthesia  over  large  areas  of  the  body,  sometimes  over 
almost  the  whole  body ;  this  is  probably  due  to  its  acting  on  the  pos- 
terior roots  of  the  cord.  It  must  be  noted  that  the  anaesthesia  is  only 
produced  by  the  local  application  of  the  drug.  The  internal  admin- 
istration only  leads  to  a  partial  loss  of  sensation  in  the  throat  and 
stomach,  and  no  anaesthesia  is  induced  by  its  action  after  it  reaches 
the  blood  vessels.  The  reason  for  this  evidently  is  that  in  order  to 
paralyze  the  sensory  fibres  and  terminations  a  considerable  amount  of 
the  drug  is  required,  but  much  less  is  necessary  to  paralyze  the  central 
nervous  system.  Even  in  the  frog,  the  sensory  terminations  are  not 
fully  paralyzed  until  all  symptoms  of  reflex  excitability  have  disap- 
peared and  total  paralysis  has  supervened. 

A  good  deal  of  discussion  has  arisen  as  to  whether  the  action  on  the  sen- 
sory terminations  is  a  specific  one,  or  whether  they  are  paralyzed  before  the 
motor  endings  simply  because  the  cocaine  comes  in  contact  with  them  first — 
whether,  in  fact,  if  both  endings  were  exposed  equally  to  the  action  of  the 
drug,  as  occurs  when  it  is  distributed  by  the  blood  vessels,  the  sensory  ter- 
minations would  be  specifically  attacked  and  the  motor  left  unaffected.  The 
action  was  at  first  supposed  to  be  a  specific  one  on  the  sensory  terminations, 
and  it  was  stated  that  cocaine  acted  on  the  sensory  terminations  in  the  same 
selective  way  as  curara  does  on  the  motor  endings.  There  seems,  however, 
to  be  no  ground  for  supposing  that  this  is  the  case.  At  the  same  time 
cocaine  possesses  a  distinct  selective  power  for  the  sensory  nerve  trunks  con- 
veying sensations  of  pain,  for  when  it  is  injected  into  the  spinal  canal,  there 
is  often  complete  insensibility  to  pain  while  warmth,  cold  and  touch  sensa- 
tions are  still  perceived  and  the  motor  functions  are  unchanged. 

When  cocaine  is  applied  locally  to  a  mucous  membrane  it  produces, 
besides  a  loss  of  sensation,  a  feeling  of  constriction  and  a  distinct  pallor 
and  contraction  of  the  vessels,  which  points  to  a  local  action  on  the 
vessel  walls. 

The  anaesthesia  produced  by  cocaine  is  comparatively  short,  but 
varies  with  the  strength  of  the  solution  applied  and  with  the  vascularity 
of  the  part ;  as  soon  as  the  cocaine  is  absorbed,  the  local  action  disap- 
pears and  sensation  returns. 


304 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


Cocaine  is  applied  to  the  Eye  more  frequently  than  to  any  other  part. 
It  produces  local  anaesthesia  here,  along  with  contraction  of  the  con- 
junctival  vessels,  and  this  is  followed  by  dilatation  of  the  pupil  and 
often  by  partial  loss  of  the  power  of  accommodation.  The  dilatation 
of  the  pupil  is  much  less  than  that  produced  by  atropine,  and  differs 
from  it  in  several  respects.  Thus,  the  light-reflex  is  preserved,  the 
pupil  contracting  in  bright  light  arid  dilating  further  in  the  dark ;  a 
number  of  drugs  which  have  little  or  no  effect  after  atropine,  contract 
the  cocainized  pupil  (pilocarpine,  muscarine,  physostigmine),  while 
atropine  dilates  it  still  further,  and  cocaine  produces  some  dilatation 
after  the  full  atropine  action  has  been  elicited.  It  is  evident,  then, 
that  the  two  drugs  produce  dilatation  by  acting  on  different  mechan- 
isms, and  although  the  way  in  which  cocaine  dilates  the  pupil  has  been 

FIG.  28. 


Diagram  of  the  innervation  of  the  iris.  P,  a  fibre  of  the  motor  oculi  passing  from  the  brain  to  the 
ciliary  ganglion  N,  in  which  it  terminates  around  a  nerve  cell,  which  sends  an  axis  cylinder  to 
terminate,  M,  in  the  circular  fibres  of  the  iris.  R,  a  spinal  nerve  fibre  issuing  from  the  lower  cervical 
cord,  running  through  the  stellate  and  inferior  cervical  ganglia  and  terminating  around  a  ganglion 
cell  in  the  superior  cervical  ganglion,  G.  The  axis  cylinder  from  this  nerve  cell  runs  to  the  iris  (pass- 
ing the  ciliary  ganglion)  and  terminates  in  fibrils  C,  on  the  radiating  fibres.  C,  is  the  point  which 
cocaine  stimulates  and  the  resultant  contraction  of  the  muscle  fibres  causes  dilation  of  the  pupil,  but 
when  strong  impulses  descend  to  M,  as  happens  when  the  eye  is  exposed  to  bright  light,  the  circular 
muscle  overcomes  the  weaker  radiating  fibres,  and  the  pupil  is  contracted.  In  the  same  way  strong 
stimulation  of  3/by  muscarine  overcomes  the  stimulation  of  C  by  cocaine,  while,  on  the  other  hand, 
when  M  is  paralyzed  by  atropine  and  the  circular  fibres  are  thus  thrown  out  of  action,  the  radiating 
muscles  are  unopposed,  and  cocaine  causes  a  greater  dilatation  than  in  the  normal  eye. 

a  matter  of  dispute,  the  great  majority  of  investigators  now  hold  that 
it  stimulates  the  terminations  of  the  dilator  fibres.  (Fig.  28.)  The 
motor  oculi  is  not  involved  in  its  effects,  unless  very  large  quantities 
are  applied,  when  its  terminations  may  be  depressed  in  the  same  way 


COCAINE.  305 

as  by  atropine  (Schultz).  A  strong  argument  in  favor  of  the  view 
given  above  has  been  found  in  the  observation  that  when  the  dilator 
nerves  degenerate,  owing  to  removal  of  the  superior  cervical  ganglion, 
cocaine  fails  to  cause  dilatation  of  the  pupil. 

Several  other  symptoms  are  produced  by  the  local  application  of 
cocaine  to  the  eye,  at  any  rate  in  some  instances.  Thus,  the  iris  ves- 
sels are  sometimes  much  constricted,  the  eye  is  more  widely  open  than 
usual,  so  that  the  white  sclerotic  is  seen  above  and  below  the  iris,  the 
whole  eyeball  is  pushed  forward  (exophthalmos),  and  the  intraocular 
tension  is  said  to  be  considerably  reduced.  All  of  these  features 
are  produced  only  after  cocaine  has  been  applied  in  considerable  quan- 
tity and  for  some  time,  and  may  be  due,  at  any  rate  in  part,  to  its 
absorption.  They  may  all  be  observed  in  the  un poisoned  animal  when 
the  cervical  sympathetic  trunk  is  stimulated,  and  therefore  seem  to  in- 
dicate a  special  action  of  cocaine  on  the  centres  or  terminations  of  this 
nerve.  All  of  these  symptoms,  except  the  anaesthesia  and  the  pallor  of 
the  conjunctiva  and  iris,  are  produced  by  the  injection  of  cocaine  as 
well  as  by  its  local  application,  but  in  this  case  are  prevented  by  pre- 
vious section  of  the  cervical  sympathetic.  Cocaine  does  not  produce 
any  dilatation  of  the  pupil  in  birds. 

Cocaine  brought  into  immediate  contact  with  nerve  terminations 
paralyzes  them,  but  this  is  true  for  so  many  other  forms  of  living  matter 
that  it  may  be  regarded  as  a  General  Protoplasm  Poison.  Thus  muscles, 
nerves,  and  nerve  ends  cease  to  contract  or  to  conduct  stimuli  when 
they  are  exposed  to  even  very  dilute  solutions  of  cocaine ;  the  ciliated 
epithelial  cells,  leucocytes,  and  spermatozoa  become  motionless ;  the 
cortical  nerve  cells  lose  their  excitability,  and  many  of  the  inverte- 
brates are  killed  by  even  a  short  exposure  to  cocaine.  The  move- 
ments of  protoplasm  in  plants  are  also  retarded  or  entirely  suppressed 
by  this  poison,  and  the  process  of  putrefaction  is  delayed  considerably. 
In  some  cases,  notably  in  the  higher  invertebrates,  the  final  depression 
is  preceded  by  a  stage  of  increased  movement,  and  it  is  said  that  the 
irritability  of  nerve  is  also  augmented  at  first.  In  other  instances, 
however,  cocaine  induces  only  depression  and  paralysis. 

Other  examples  of  this  destructive  action  are  also  seen  in  the  thera- 
peutic use  of  cocaine,  for  the  cornea  is  often  rendered  somewhat 
cloudy  from  its  application,  and  its  subcutaneous  injection  is  sometimes 
followed  by  necrosis.  Victims  of  the  cocaine  habit  often  show  nu- 
merous scars  on  the  arms  and  legs  from  this  local  gangrene,  although 
this  is  probably  often  due  to  unsterilized  syringes  rather  than  to  the 
solution. 

Most  of  the  other  natural  alkaloids  resemble  cocaine  in  many  points  of 
their  action,  as  far  as  they  have  been  investigated,  but  some  of  the  artificial 
compounds  present  divergences  from  the  general  type.  Thus  a  number  of 
them  do  not  produce  anaesthesia,  although  most  of  the  nearly  allied  forms 
cause  the  characteristic  changes  in  the  liver  cells  ;  some  of  them  depart  en- 
tirely from  the  typical  cocaine  action. 

Cocamine  is  often  said  to  be  a  cardiac  poison,  but  its  action  on  the  heart 
seems  to  resemble  in  general  that  of  cocaine.  It  has,  however,  a  much  more 
20 


306  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

intense  action  on  muscular  tissue,  which  it,  like  caffeine,  throws  into  rigor 
mortis.  Its  anaesthetic  power  is  very  small.  Some  authorities  regard  the  mus- 
cular action  of  caffeine  as  an  important  factor  in  its  preventing  fatigue,  and  the 
presence  of  cocamine  in  the  coca  leaves  might  be  used  to  explain  the  similar 
effects  induced  by  these,  but  the  quantity  is  probably  too  small  to  have  any 
noticeable  action. 

Benzoylecgonine  is  a  comparatively  weak  body,  which  produces  symptoms 
resembling  caffeine — increased  reflex  excitability,  muscular  stiffness,  and  rigor — 
and  ecgonine  is  still  less  active,  but  elicits  in  frogs  similar  effects. 

Tropacocaine  resembles  cocaine  very  closely  in  its  general  action,  but  is 
less  poisonous.  It  produces  local  anaesthesia  more  rapidly  but  for  a  shorter 
time  than  cocaine,  and  causes  less  dilatation  of  the  pupil. 


PREPARATIONS. 

Coca  (IT.  S.  P.),  the  dried  leaves  of  Ery throxylon  coca,  containing  1-1  per 
cent,  of  cocaine. 

Fluidextractum  Cocce  (U.  S.  P.),  2-4  c.c.  Q-l  fl.  dr.). 

Extractum  Cocce  Liquidum  (B.  P.),  £-1  fl.  dr. 

Vinum  Cocce  (U.  S.  P.),  16  c.c.  (4  fl.  drs.). 

COCAINA  (U.  S.  P.,  B.  P.),  an  alkaloid  (C17H21NO4)  obtained  from  the  leaves 
of  Erythroxylon  coca  and  its  varieties,  forming  colorless  crystals  with  a  bitter 
taste  followed  by  numbness  ;  insoluble  in  water,  soluble  in  alcohol. 

COCAINE  HYDROCHLORIDUM  (U.  S.  P.,  B.  P.)  (C1?H21NO4HC1),  colorless 
crystals,  very  soluble  in  water  and  alcohol ;  watery  solutions  cannot  be  boiled  as 
the  alkaloid  tends  to  decompose,  0.01-0.03  G.  (£-£  gr.). 

Lamellae  Cocaince  (B.  P.),  each  contains  -fa  gr.  of  the  hydrochloride. 

Injectio  Cocaince  Hypodermica  (B.  P.),  10  per  cent.,  2-5  mins. 

Unguentum  Cocaince  (B.  P. ),  4  per  cent. 

Oleatum  Cocaince  (U.  S.  P. ),  5  per  cent. 

Trochisci  Kramerice  et  Cocaince  (B.  P. ),  each  contains  -fa  gr.  of  the  hydro- 
chloride. 

The  Therapeutic  Uses  of  cocaine  are  almost  all  dependent  on  its  an- 
aesthetic action.  It  has  been  suggested  as  a  brain  stimulant  in  various 
conditions  of  mental  depression,  but  has  not  been  widely  used  for  this 
purpose,  which  is  better  served  by  the  less  dangerous  caffeine.  A 
wine  containing  coca  extract  is  often  used  in  domestic  medicine  as  a 
"  general  tonic,"  and  has  repeatedly  given  rise  to  the  cocaine  habit. 

Its  anaesthetic  properties  render  it  extremely  important.  In  oph- 
thalmic surgery  it  is  used  very  largely  both  during  operations  and  to 
alleviate  pain,  and  occasionally  to  constrict  the  vessels  of  the  iris  in  in- 
flammatory conditions.  For  complete  anaesthesia  a  4  per  cent,  solution 
may  be  employed,  while  to  allay  pain  one  of  1-2  per  cent,  is  all  that 
is  necessary.  The  anaesthesia  is  of  short  duration,  generally  setting  in 
after  5-7  minutes  and  passing  off  20-30  minutes  after  the  application 
of  the  drug.  Occasionally  cocaine,  especially  in  strong  solution,  pro- 
duces a  certain  amount  of  opacity  of  the  cornea,  and  it  is  stated  that 
wounds  heal  less  readily,  and  irritant  antiseptics  are  more  dangerous 
with  cocaine  than  without  it.  This  may  sometimes  be  due  to  the  use 
of  impure  cocaine,  but  it  may  be  noted  that  cocaine  is  a  protoplasm 
poison,  and  may  therefore  lessen  the  resistance  of  the  tissues  with 
which  it  comes  in  contact.  The  usual  explanation  given  that  cocaine 
paralyzes  sensation  in  the  cornea,  and  thus  prevents  the  reflex  winking 


COCAINE.  307 

which  removes  foreign  bodies  from  the  surface  and  keeps  the  eye  moist, 
is  obviously  insufficient,  as  the  anaesthesia  is  of  but  short  duration. 
The  dilatation  of  the  pupil  produced  by  cocaine  is  much  less  complete 
than  that  under  atropine,  and  can  only  be  taken  advantage  of  in  diag- 
nosis by  using  very  dim  light,  as  the  pupil  contracts  in  bright  light 
almost  to  its  normal  size.  On  the  other  hand  cocaine  is  much  less 
injurious  in  glaucoma  and  the  dilatation  can  be  removed  at  once  by 
the  instillation  of  a  few  drops  of  physostigmine. 

In  the  nose,  throat  and  larynx,  cocaine  is  used  in  a  solution  of  4 
per  cent.,  sometimes  10-20  per  cent.,  and  anesthesia  is  obtained  with 
greater  difficulty  than  in  the  eye,  but  the  local  contraction  of  the  ves- 
sels is  often  of  great  service.  Cocaine  is  used  largely  in  operative 
procedure  here  and  also  in  the  treatment  of  irritable  conditions  of  the 
respiratory  passages,  such  as  hay  fever.  In  the  urethra,  rectum  and 
vagina,  cocaine  may  also  be  used  either  as  an  anaesthetic  or  to  relieve 
pain  temporarily.  It  is  sometimes  of  service  in  painful  or  itching 
skin  diseases,  but  care  must  be  taken  not  to  apply  it  to  large  broken 
surfaces,  otherwise  symptoms  of  poisoning  may  follow.  The  local 
action  on  the  stomach  is  often  valuable  in  checking  vomiting  due  to 
gastric  irritation. 

For  many  years  after  its  introduction  as  a  local  anaesthetic  in  1884, 
its  use  was  practically  limited  to  minor  operations  in  the  nose  and 
throat  and  to  ophthalmic  surgery,  few  general  surgeons  venturing  on  its 
application  in  other  fields.  Within  the  last  few  years,  however,  its  use 
has  undergone  a  wide  extension,  so  that  almost  all  the  major  surgical 
operations  have  been  performed  under  it,  and  local  anaesthesia  by  means 
of  cocaine  or  eucaine  has  now  become  a  rival  of  ether  and  chloroform. 
Occasionally  partial  local  anaesthesia  is  combined  with  the  administra- 
tion of  small  quantities  of  chloroform  or  ether,  which  are  insufficient 
to  produce  complete  unconsciousness,  but  cause  a  numbing  of  the 
sensation,  which,  together  with  the  local  action,  permits  of  a  painless 
operation.  At  first  strong  solutions  were  injected  to  prepare  the  way 
for  the  knife,  each  step  forward  in  the  operation  being  preceded  by  an 
injection  of  cocaine  to  induce  anaesthesia  of  the  layer  of  tissue  to  be 
incised.  But  this  method,  which  has  been  used  chiefly  by  Reclus, 
required  dangerous  quantities  of  the  drug,  and  is  now  scarcely  used 
except  for  minor  operations  in  which  a  single  injection  is  sufficient. 
A  more  satisfactory  method  of  local  anaesthesia  for  operative  purposes 
has  been  introduced  by  Schleich  under  the  name  of  infiltration 
anesthesia.  A  large  quantity,  sometimes  as  much  as  200  c.c.  of  a 
solution  containing  0.01  per  cent.1  of  cocaine  and  0.8  per  cent,  of 
sodium  chloride  is  allowed  to  permeate  the  tissues  through  a  fine 
hypodermic  needle.  Only  very  slight  pressure  is  required  and  the 
whole  of  the  surrounding  structures  become  swollen  and  oedematous 
and  can  be  cut  into  without  pain.  Much  of  the  fluid  escapes  through 
the  incisions  and  no  symptoms  of  poisoning  arise.  Schleich  attributed 
the  anaesthesia  partly  to  the  pressure  exerted  by  the  solution  and  partly 

1  Some  operators  use  a  0. 1  per  cent,  solution  and  then  less  is  injected. 


308  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION 

to  the  imbibition,  but  later  investigators  have  found  it  to  be  dependent 
on  the  cocaine  alone.1  Another  method  (regional  anaesthesia)  is  the 
injection  of  cocaine  into  the  immediate  neighborhood  of  the  nerve 
supplying  the  part  to  be  operated  on.  Complete  local  anaesthesia  is 
obtained,  and  shock  is  less  liable  to  occur  than  when  general  anaesthe- 
sia is  induced  (Crile).  This  method  has  been  used  extensively  in 
operations  on  the  foot  and  hand,  for  which  it  is  admirably  suited ;  it  is 
difficult  to  adapt  it  to  other  parts  of  the  body.  The  local  action  in 
both  infiltration  and  regional  anaesthesia  may  be  augmented  and  the 
danger  of  general  poisoning  lessened  by  retarding  the  circulation  in 
the  part  to  be  operated  on.  This  may  be  done  by  applying  an 
Esmarch  bandage  above  it  when  a  limb  is  involved,  or  by  the  applica- 
tion of  cold  by  means  of  ethyl  chloride  ;  but  the  best  results  are 
obtained  by  using  a  1  per  mille  solution  of  adrenaline  along  with 
cocaine.  This  contracts  the  vessels  and  arrests  the  circulation  locally, 
and  the  cocaine  thus  remains  longer  unabsorbed.  Braun  recommends 
3  drops  of  1  per  mille  adrenaline  solution  to  50  c.c.  of  cocaine  solu- 
tion for  infiltration. 

After  it  was  found  that  the  nerve  impulses  from  the  periphery  to 
the  central  nervous  system  could  be  blocked  by  the  injection  of 
cocaine  into  the  peripheral  nerves,  the  next  step  was  to  obstruct  them 
higher  in  their  course  by  applying  it  to  the  spinal  roots  (subarachnoid 
anaesthesia).  The  first  to  attempt  this  was  Corning  of  New  York, 
but  the  development  of  the  procedure  is  due  to  Bier  and  Turner.  A 
long  hollow  needle  is  passed  into  the  spinal  canal  between  the  laminae 
of  the  lumbar  vertebrae  and  1  c.c.  of  a  2  per  cent,  solution  of  cocaine 
hydrochlorate  is  injected,  after  the  withdrawal  of  an  equivalent  amount 
of  cerebrospinal  fluid.  The  actual  amount  of  cocaine  injected  is  thus 
0.02  G.  (J  gr.).  Within  a  few  minutes  numbness  begins,  generally  in  the 
feet  at  first,  but  sometimes  in  the  lower  part  of  the  trunk ;  it  spreads 
upwards  rapidly  until  sensibility  to  pain  is  lost  everywhere  below  the 
diaphragm  and  sometimes  in  the  thorax ;  in  some  cases  even  the  head 
has  been  found  anaesthetized.  The  sensations  induced  by  warmth  and 
cold  are  less  quickly  affected,  touch  is  preserved  to  some  extent  and 
the  limbs  can  be  moved  readily,  though  the  movements  are  carried 
out  more  slowly  than  usual ;  the  consciousness  is  unimpaired.  This 
condition  lasts  from  half  an  hour  to  an  hour  and  then  sensation 
returns  gradually.  "  In  the  beginning  of  the  action  some  muscular 
twitching  is  often  seen,  and  the  muscles  are  never  relaxed  as  they  are 
nnder  chloroform  or  ether.  Vomiting  occurs  in  a  large  proportion  of 
cases  either  during  or  after  the  operation,  and  persistent  headache  is 
generally  present.  The  cocaine  is  believed  to  act  on  the  posterior 
nerve  roots  and  not  on  the  cord  itself.  The  cerebrospinal  fluid  has 
been  found  to  contain  a  large  number  of  polynuclear  leucocytes  after 
the  injection  and  resumes  its  normal  limpid  character  only  after  several 
days.  This  method  of  anaesthesia  has  been  used  in  a  large  number  of 

1  Heinze  showed  that  the  morphine  contained  in  Schleich's  original  fluid  was  super- 
fluous. 


COCAINE.  309 

operations,  some  of  them  of  the  gravest  nature ;  it  has  also  been  sub- 
stituted for  general  anesthesia  in  labor. 

Of  these  methods,  Schleich's  infiltration  has  been  most  widely 
adopted  and  is  admirably  suited  for  minor  operations.  It  is  the  safest 
method  available  for  most  of  these,  for  the  amount  of  cocaine  injected 
ought  not  to  be  sufficient  to  induce  poisonous  symptoms,  and  should 
never  exceed  20  mg.  (J  gr.)  and  much  of  this  escapes  by  the  incision. 
It  requires  some  experience  to  induce  complete  insensibility  to  pain  by 
this  method  and  the  operation  has  to  be  interrupted  at  intervals  to  permit 
of  further  injections.  Some  headache  and  nausea  are  occasional  sequelae. 
When  general  anaesthesia  is  contraindicated,  infiltration  may  be  adopted 
in  major  operations,  while  on  the  other  hand  it  is  often  contraindicated 
in  minor  operations  where  there  is  any  possibility  of  complications,  or 
where  the  anxiety  and  nervousness  of  the  patient  are  likely  to  interfere 
with  the  proceedings.  Subarachnoid  or  intraspinal  cocainization  is 
still  on  trial,  and  while  it  has  been  enthusiastically  praised  by  some  of 
its  sponsors,  it  has  in  general  been  regarded  as  a  hazardous  method. 
Several  fatalities  are  said  to  have  resulted  from  it,  and  headache  and 
nausea  very  often  persist  for  many  hours  after  the  operation.  It  seems 
probable  that  it  will  in  the  future  attract  less  attention  than  it  has 
recently,  and  will  be  regarded  as  a  last  resort  to  be  used  when  special 
circumstances  contraindicate  the  general  anesthetics  and  operation  is 
imperative. 

Cocaine  Habit.  —  Since  the  introduction  of  cocaine  into  general  thera- 
peutic use,  numerous  cases  of  the  formation  of  a  habit  similar  to  that 
of  opium  or  morphine,  have  been  recorded.  Some  of  these  have  been 
due  to  the  attempt  to  substitute  cocaine  for  morphine  in  the  treatment 
of  chronic  morphinism,  the  treatment  often  resulting  in  the  develop- 
ment of  an  irresistible  craving  for  both  alkaloids.  The  symptoms  of 
cocainism  generally  begin  with  digestive  disorders,  loss  of  appetite, 
salivation  and  emaciation,  but  the  more  important  changes  occur  in  the 
central  nervous  system,  which  apparently  undergoes  degeneration  simi- 
lar to  that  seen  in  chronic  morphine  poisoning.  Sleeplessness,  tremors 
and  occasionally  convulsions,  hallucinations,  insanity  and  delirium  have 
been  noted  after  long  abuse,  along  with  indefinite  disturbances  of  sen- 
sation and  motion.  The  treatirient  of  these  cases  is  the  withdrawal  of 
the  drug,  and  this  can  generally  be  done  without  the  production  of  any 
special  symptoms,  though  it  is  sometimes  followed  by  great  depression. 
This  treatment  is  much  facilitated  by  sending  the  patient  to  a  special 
resort,  and,  in  fact,  is  almost  hopeless  without  his  isolation. 

Acute  Cocaine  Poisoning  is  treated  purely  symptomatically.  Amyl- 
nitrite  has  been  advised  when  the  blood-pressure  seems  much  elevated, 
while  for  the  convulsive  attacks  small  quantities  of  chloroform  or  ether 
may  be  necessary.  Of  course,  the  stomach  ought  to  be  evacuated 
first  of  all  if  the  drug  has  been  taken  by  the  mouth. 


310  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Substitutes  for  Cocaine. 

Some  artificial  alkaloids  have  recently  been  introduced  as  local  an- 
aesthetics instead  of  cocaine.  The  best  known  of  these  is  Eucaine 
(C15H21NO2y  which  is  much  less  poisonous  than  cocaine  and  differs 
from  it  in  many  points  in  its  general  action.  In  animals  poisoned 
with  large  doses  the  central  nervous  system  is  first  stimulated  and  then 
paralyzed ;  the  pulse  is  slowed  from  direct  action  on  the  cardiac  mus- 
cle, and  the  blood-pressure  falls.  The  terminations  of  the  motor  nerves 
are  paralyzed  in  frogs,  but  only  after  the  central  nervous  system.  As 
a  local  anaesthetic  it  is  almost  as  efficient  as  cocaine,  and  differs  from  it 
in  not  constricting  the  vessels  or  dilating  the  pupil.  The  intraocular 
pressure  is  said  to  be  lessened,  but  this  is  not  yet  satisfactorily  deter- 
mined. A  1-2  per  cent,  solution  of  the  hydrochlorate  is  used  in  the 
eye,  2-5  per  cent,  for  other  mucous  surfaces  and  for  subcutaneous  in- 
jection. Eucaine  may  be  employed  in  1  per  cent,  solution  instead  of 
cocaine  for  infiltration  anaesthesia,  and  is  less  poisonous  and  can  be  dis- 
infected by  boiling. 

The  Orthoforms  are  still  more  recently  introduced  local  anaesthetics, 
which  may  be  mentioned  here,  although  they  resemble  cocaine  only  in 
their  action  on  the  sensory  terminations.  They  are  methylesters  of 
amidooxybenzoic  acid  (C6H3OH(NH2)  (COOCH3)),  differing  only  in 
the  positions  of  the  hydroxyl  and  amido  groups ;  ancesthesin,  the 
ethylester  of  amidobenzoic  acid,  and  many  other  similar  esters  have 
more  or  less  local  anaesthetic  power.  Several  other  aromatic  derivatives 
have  long  been  known  to  have  some  numbing  or  anaesthetic  properties, 
but  have  scarcely  been  used  in  therapeutics  for  this  purpose.  Even 
carbolic  acid  has  a  distinct  numbing  effect,  and  some  of  the  antipy- 
retics have  been  proposed  for  use  in  ophthalmology.  Orthoform  is  a 
white  crystalline  powder  which  has  no  taste  or  smell  and  is  only 
very  slightly  soluble  in  water.  It  is  used  as  a  dusting  powder  or  in 
ointment  (10  per  cent.),  and  is  applied  to  painful  surfaces,  such  as 
abrasions,  ulcers  or  burns,  either  on  the  skin  or  on  the  visible  mucous 
membranes  (for  instance,  in  laryngeal  ulceration).  In  ulcer  or  cancer 
of  the  stomach,  it  has  also  been  taken  internally  (0.1  G.  in  powder  or 
tablets),  and  gives  relief  from  the  suffering.  It  is  somewhat  anti- 
septic and  seems  to  be  practically  devoid  of  poisonous  properties, 
except  that  slight  corrosion  is  sometimes  induced  around  the  point  of 
application.  It  has  little  or  no  effect  on  the  sensibility  of  the  unbroken 
skin,  and  its  insolubility  precludes  its  use  by  subcutaneous  injection. 
The  anaesthesia  begins  almost  as  soon  as  that  induced  by  ordinary 
cocaine  solutions,  but  lasts  very  much  longer,  because  orthoform  is 
dissolved  and  removed  from  the  surface  very  slowly ;  thus  a  single 
application  of  the  powder  causes  anaesthesia  for  many  hours,  or  even 
for  some  days.  On  the  other  hand,  orthoform  fails  to  penetrate  the 
mucous  membranes  as  cocaine  does,  and  therefore  only  anaesthetizes 
when  it  comes  into  actual  contact  with  exposed  nerve  ends. 

1  Alpha-eucaine  (C,9H27NO4)  was  formerly  used,  but  induces  irritation  at  first,  and 
is  now  seldom  met  with.  Eucaine  was  introduced  as  Beta-eucaine. 


PILOCARPINE  AND  MUSCARINE.  311 

Another  series  of  local  anaesthetics  has  been  introduced  by  Trplldenier 
under  the  name  of  Acoines.  They  are  derivations  of  phenylguanidin  and 
are  said  to  be  much  less  poisonous  than  cocaine  and  to  induce  complete  an- 
aesthesia of  the  cornea  and  conjunctiva  and  also  to  be  available  for  infiltration 
anaesthesia.  Holocaine,  a  derivative  of  phenacetine,  has  been  recommended 
in  ophthalmological  operations,  but  is  more  poisonous  than  eucaine,  and 
presents  no  equivalent  advantages. 

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Chadbourne.     Brit.  Med.  Journ.,  1892,  ii.,  p.  402.     (Tropacocaine.) 
Vinci.     Virchow's  Arch.,  cxlv.,  p.  78.     (Eucaine.)     Arch.  f.  Anat.  u.  Phys.,  1897, 
p.  163.     Virchow's  Arch.,  cxlix.,  p.  217;  cliv.,  p.  549. 

Einhorn  u.  Heinz.     Munch,  med.  Woch.,  1897,  p.  931.     (Orthoform.) 
Soulier  et  Guinard.     Arch,  internat.  de  Pharmacodyn.,  vi.,  p.  1. 
Wiechowski.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi.,  p.  154. 
Heinze.     Virchow's  Arch.,  cliii.,  p.  466. 
Trolldenier.     Therap.  Monatsh.,  1899,  p.  36.     (Acoines.) 
Sraun.     Arch.  f.  klin.  Chir.,  Ivii.,  p.  370 ;  Ixix.,  p.  541. 
Bier.     Ibid.,  Ixiv.,  p.  236. 
Valenti.     Arch.  Ital.  de  Biol.,  xxxix.,  p.  253. 
Orile.     Journ.  Amer.  Med.  Assoc.,  Feb.  22,  1902. 
Lea.     Journ.  of  Obstet.  and  Gynecol.,  i.,  p.  71. 
Terrett.     American  Medicine,  1901,  ii.,  p.  417. 

XIV.     PILOCARPINE  AND  MUSCARINE. 

Pilocarpine  and  muscarine,  two  alkaloids  of  very  different  chemical 
constitution,  possess  similar  properties  from  a  pharmacological  point 
of  view.  Pilocarpine  (CUH16N2O2) 1  is  found  along  with  Isopilocar- 
pine  in  the  leaves  of  several  species  of  Pilocarpus. 

Muscarine,  the  alkaloid  of  one  of  the  poisonous  mushrooms,2  Agari- 
cus  muscarius,  or  Amanita  muscaria,  is  very  closely  related  chemically 
to  choline,  which  is  a  constituent  of  several  animal  tissues.  It  may 
probably  be  represented  by  the  formula 

CH—  (OH)2 


JH. 


[2-N(CH3)3OH 

1  The  structural  formula  of  pilocarpine  is  not  yet  definitely  determined.      Pilocarpi- 
dine  has  been  isolated  from  the  leaves  of  Pilocarpus  Jaborandi  only  and  is  practically 
inert.     Jaborine  was  formerly  stated  to  occur  with  pilocarpine  and  to  possess  an  action 
resembling  that  of  atropine,  but  more  recent  investigators  have  failed  to  confirm  either 
of  these  statements. 

2  Muscarine  is  accompanied  in  the  Amanita  by  another  poison  which  differs  from  it- 
in   inducing  convulsions  and   other  symptoms  of  central   nervous    stimulation;   the 
symptoms  of  amanita  poisoning  are  a  mixture  of  those  caused  by  these  two  poisons 
(Harm  sen). 


312  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

A  substance  almost  identical  with  muscarine  from  the  chemical  stand- 
point has  been  prepared  by  the  oxidation  of  choline,  but  this  synthetic 
muscarine  differs  in  its  action  from  the  natural  alkaloid  in  several 
respects.  A  number  of  other  nearly  related  bodies  (trimethylammo- 
nium  bases)  resemble  muscarine  in  some  points  of  their  action,  but 
are  not  so  poisonous,  and  fail  to  act  on  several  of  the  organs  affected 
by  the  base  derived  from  the  mushroom. 

Muscarine,  pilocarpine  and  isopilocarpine  resemble  each  other  in 
action ;  muscarine  is  much  more  poisonous  than  pilocarpine,  which  is 
again  eight  times  as  active  as  isopilocarpine. 

Pilocarpine  and  muscarine  stimulate  the  terminations  of  certain 
nerves  supplying  mistriated  muscle  (except  that  of  the  vessels),  the 
heart  and  secretory  epithelium.  Their  effects  are  therefore  diametri- 
cally opposed  to  those  of  atropine  in  the  peripheral  organs. 

Symptoms.— The  symptoms  of  poisoning  in  man 'commence  with  a 
very  marked  secretion  of  saliva,  followed  soon  after  by  excessive  per- 
spiration and  a  flow  of  tears.  After  muscarine  and  sometimes  after 
pilocarpine,  nausea,  retching  and  vomiting,  pain  in  the  abdomen  and 
violent  movement  of  the  intestines  causing  profuse  watery  evacuations, 
are  next  observed.  The  pulse  is  sometimes  quickened,  sometimes  very 
slow  and  irregular ;  the  pupil  is  contracted,  and  the  sight  is  accommo- 
dated for  near  objects.  The  respiration  is  often  quick  and  dyspnoeic, 
and  rales  may  be  heard  over  the  bronchi,  denoting  an  accumulation  of 
mucus  in  them.  Giddiness  and  confusion  of  ideas  are  complained  of, 
and  after  pilocarpine  tremors  and  feeble  convulsive  movements  are 
sometimes  observed,  but  the  nervous  symptoms  are  not  so  conspicuous 
as  those  from  the  peripheral  organs.  Eventually  the  respiration  be- 
comes slower  and  great  weakness  in  the  movements  manifests  itself, 
but  the  consciousness  remains  more  or  less  perfect  till  the  breathing 
ceases. 

Action. — The  salivary  and  lachrymal  Glands,  the  mucous  glands  of 
the  mouth,  throat,  nose  and  deeper  respiratory  passages,  the  gastric 
secretory  glands,  the  pancreas,  and  probably  the  intestinal  glands,  all 
secrete  copiously  after  muscarine  and  pilocarpine.  The  sweat  glands 
and  the  ceruminous  glands  of  the  ears  are  likewise  roused  to  unwonted 
activity,  and  many  other  glandular  structures  are  also  stimulated.1 

In  most  cases  the  solids  of  the  secretions  are  increased  as  well  as 
the  fluids,  although  to  a  somewhat  less  extent.  The, bile,  the  urine 
and  the  milk  do  not  seem  to  be  affected  directly  by  pilocarpine  and 
muscarine,  although  they  may  be  reduced  in  amount  or  otherwise 
modified  by  the  withdrawal  of  large  quantities  of  fluid  from  the  body 
by  other  channels. 

After  a  small  quantity  of  atropine,  pilocarpine  and  muscarine  in 
ordinary  quantities  produce  no  increase  in  any  of  the  secretions.  This 
indicates  that  the  seat  of  action  of  these  poisons  is  not  the  secretory 
cells,  for  it  has  been  shown  that  atropine  paralyzes  only  the  termina- 

1  A  curious  example  of  this  has  been  shown  by  Dreser  to  occur  in  the  fish,  in  which 
the  swimming  bladder  secretes  more  oxygen  than  usual. 


PILOCARPINE  AND  MUSCARINE.  313 

tions  of  the  secretory  nerves  and  leaves  the  cells  uninjured.  On  the 
other  hand,  section  of  the  secretory  nerves  does  not  alter  materially 
the  action  of  pilocarpine  or  muscarine,  for  the  secretion  of  perspira- 
tion in  the  foot  of  the  cat  is  increased  by  pilocarpine  even  after  section 
of  the  sciatic  nerve.  The  seat  of  action  of  pilocarpine  and  muscarine 
is  therefore  the  terminations  of  the  secretory  nerves — the  minute  fibrils 
which  ramify  between  the  epithelial  cells  ancTper liaps  even  enter  them. 
These  fibrils  are  stimulated  by  the  members  of  this  group  and  para- 
lyzed by  atropine,  and  these  two  series  therefore  form  antidotes  to  one 
another. 

The  salivary  secretion  may  amount  to  half  a  litre  or  more  in  the 
course  of  2-3  hours  after  an  injection  of  pilocarpine,  while  the  skin 
and  lungs  excrete  even  a  larger  quantity  of  fluid  in  the  same  time. 
The  weight  is  thus  considerably  reduced  by  pilocarpine  owing  to  the 
loss  of  fluid,  which  may,  according  to  some  authors,  amount  to  2-4 
kilogrammes  (4J-9  Ibs.)  after  a  single  dose. 

The  secretion  of  the  milk  is  not  increased  by  pilocarpine,  but  the 
percentage  of  sugar  in  it  is  stated  to  be  larger  than  usual.  Ube 
sugar  of  the  blood  has  been  found  increased  by  pilocarpine,  and  this 
lias  been  attributed  to  its  acting  on  the  terminations  of  the  nerves  in 
the  liver  which  regulate  the  glycogenic  functions  of  that  organ. 

The  increased  activity  of  the  glands  is  accompanied  by  an  accelera- 
tion of  the  blood  current  through  them,  but  this  is  a  result  of  their 
stimulation  from  any  cause  whatever,  and  is  probably  not  due  to  the 
direct  action  of  the  alkaloids  on  the  vessels.  The  redness  of  the  skin, 
especially  of  the  face,  so  often  observed  after  pilocarpine,  may  perhaps 
be  explained  in  this  way,  as  an  accompaniment  of  the  augmented  ac- 
tivity of  the  sweat  glands. 

It  was  formerly  supposed  that  pilocarpine  acted  on  the  same  structures  as 
nicotine — the  sympathetic  ganglia — but  this  is  disproved  by  the  sweat  secre- 
tion of  the  foot  after  section  of  the  sciatic,  for  no  sympathetic  ganglia  have 
been  found  in  connection  with  these  sweat  glands  except  those  in  the  pelvis. 
Another  question  which  has  been  the  subject  of  prolonged  and  somewhat 
bitter  discussion  is  whether  pilocarpine  and  muscarine  can  act  at  all  after 
atropine.  It  seems  now  to  be  admitted  that  while  minute  quantities  of 
the  latter  stop  secretion  set  up  by  ordinary  doses  of  pilocarpine  and  mus- 
carine, yet  either  of  these  in  very  large  quantities  will  reinstate  it,  and  this 
alternation  of  stimulation  and  depression  may  be  repeated  a  number  of 
times. 

After  a  prolonged  stage  of  stimulation  large  quantities  of  pilocarpine  or 
muscarine  eventually  paralyze  the  nerve  terminations,  and  the  secretions  are 
therefore  diminished  or  stopped  entirely.  But  this  never  occurs  save  in  ex- 
periments on  animals,  for,  as  a  general  rule,  the  respiration  is  paralyzed  by 
smaller  quantities  than  are  necessary  to  elicit  this  feature. 

Muscle.  —  Nausea  and  discomfort  in  the  stomach,  followed  by  retch- 
ing and  vomiting,  are  rarely  seen  after  pilocarpine,  but  form  some  of 
the  earliest  symptoms  of  muscarine  poisoning.  They  are  not  produced 
by  the  saliva  swallowed,  as  was  formerly  supposed,  but  by  a  stimula- 
tion of  the  terminations  of  the  pneumogastric  in  the  muscular  coats  of 


314  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

the  stomach,  similar  to  that  of  the  terminations  of  the  secretory  nerves. 
This  is,  perhaps,  incapable  in  itself  of  producing  complete  evacuation 
of  the  stomach,  but  may  set  up  a  reflex  contraction  of  the  muscles  of 
the  abdominal  wall  which  accomplishes  it. 

C  The  intestines  are  also  set  in  unusually  active  movement  by  a  similar 
"/process,  and'  repeated  evacuation  of  their  contents  follows.  These 
are  at  first  of  firm  consistency,  but  later,  as  the  continued  peristalsis 
carries  down  the  contents  of  the  small  intestine,  which  have  not  lain 
long  enough  in  the  bowel  to  allow  of  the  absorption  of  their  fluid,  the 
faeces  contain  more  water  than  usual.  This  fluidity  of  the  stools  may 
also  be  due  in  part  to  an  augmentation  of  the  intestinal  secretion,  but 
this  has  not  been  satisfactorily  demonstrated.  Even  after  the  bowel 
has  been  completely  evacuated,  the  persistent  peristalsis  betrays  itself 
in  painful  straining. 

/^  The  muscle  of  a  number  of  other  organs  contracts  after  pilocarpine 
\  or  muscarine,  also,  it  is  believed,  from  stimulation  of  the  nerve  ter- 
xr  minations.  Thus  the  ^(^pi.  bladder*  bronchial  muscles,  and  possibly 
I  the  uterus,  are  contracted,  and  in  the  case  of  the  bladder  repeated 
\evacuation  and  straining  may  occur.  Of  much  greater  importance 
than  these  is  the  effect  of  pilocarpine  and  muscarine  on  the  eye.  In 
poisoning  with  these  and  also  on  local  application,  the  pupil  becomes 
extremely  narrowed,  and  at  the  same  time  the  ciliary  muscle  contracts 
so  that  the  lens  is  accommodated  for  short  distances.  Both  of  these 
phenomena  are  due  to_££imjiajtiQ_n  pf  the  terminations  of  the  mofor 
oculi  in  the  intraocular  muscles  (see  Fig.  26,  p.  287) ;  they  are  not 
equally  easily  elicited,  however,  for  according  to  Krenchel,  muscarine 
acts  on  the  ciliary  muscle  much  more  readily  than  on  the  pupil,  so  that 
occasionally  the  sight  may  be  accommodated  for  short  distances  while 
the  pupil  remains  fairly  wide.  The  intraocular  pressure  is  reduced  by 
muscarine  and  pilocarpine,  although  they  may  increase  it  at  first. 
This  has  riot  been  explained,  but  is  often  said  to  be  associated  with  the 
changes  in  the  pupil,  myosis  (contraction  of  the  pupil)  being  generally 
attended  by  a  reduced  tension.  The  stimulant  action  of  pilocarpine  on 
the  terminations  of  the  motor  oculi  terminates  in  depression  and  con- 
sequent slight  widening  of  the  pupil. 

All  these  muscular  phenomena  are  prevented  by  the  previous  ad- 
ministration of  atropine.  This  antagonistic  action  has  been  carefully 
studied  in  the  eye,  where  it  is  found  that  after  pilocarpine  has  pro- 
duced contraction  of  the  pupil,  the  administration  of  very  small  quan- 
tities of  atropine  is  followed  by  dilatation.  Strong  pilocarpine  solution 
again  dropped  into  the  eye  will  again  reduce  the  size  of  the  pupil,  but 
the  quantity  required  is  vastly  more  than  in  the  normal  eye,  and  this 
second  contraction  may  again  be  removed  by  comparatively  small 
quantities  of  atropine.  In  the  bird's  pupil,  in  which  the  muscle  is 
striated,  muscarine  and  pilocarpine  have  no  effect,  the  terminations  of 
the  nerves  being  evidently  different  from  those  in  mammals. 

The  action  of  pilocarpine  and  muscarine  on  the  Circulation  presents 
some  differences  in  different  species  of  animals.  On  the  applica- 


PILOCARPINE  AND  MUSCARINE.  315 

tion  of  either  to  the  frog's  heart,  its  rhythm  is  at  once  slowed,  the 
diastolic  pause  being  much  increased  in  length  and  the  contractions 
lessened  in  force.  Soon  the  heart  ceases  to  beat  entirely,  although 
irritation  of  its  muscle  by  mechanical  or  chemical  means  elicits  one  or 
more  contractions.  A  number  of  drugs  which  stimulate  the  heart 
muscle,  such  as  physostigmine  or  digitalin,  induce  weak  rhythmical 
contractions,  but  atropine  in  the  minutest  quantities  restores  the  heart 
to  its  normal  rhythm  and  strength.  The  symptoms  produced  are  ex- 
actly those  seen  on  stimulation  of  the  vagus  by  electrical  shocks,  and 
muscarine  has  long  been  believed  to  act  by  stimulation  of  the  inhibi- 
tory mechanism  in  the  heart.  It  is  generally  stated  that  the  site  of 
its  action  is  the  ganglia  on  the  course  of  the  vagus,  but  this  is  incor- 
rect, for  muscarine  acts  on  the  apex  of  the  frog's  ventricle,  in  which 
no  ganglia  whatever  have  been  found.  Muscarine,  therefore,  stimu- 
lates the  terminations  of  the  vagus  fibres  in  the  heart  muscle,  and 
thus  produces  slowing  and  eventually  standstill.  Atropine  removes 
this  standstill  by  paralyzing  the  terminations,  but  larger  quantities  of 
muscarine  or  pilocarpine  will  again  overcome  the  atropine  action  and 
restore  the  standstill  or,  at  any  rate,  the  slow  pulse.  Digitalin  and 
its  allies  remove  the  standstill  by  increasing  the  irritability  of  the 
muscle  until  the  inhibition  can  no  longer  hold  the  heart  in  check,  but 
throughout  the  rhythm  caused  by  these  the  activity  of  the  vagus  can 
be  seen  in  the  slowness  of  the  beat  and  the  prolongation  of  the  diastole. 
The  vagus  ends  are  eventually  paralyzed  by  pilocarpine  and  the  heart 
resumes  its  normal  rate.  Larger  quantities,  however,  again  slow  it 
owing  to  direct  action  on  the  cardiac  muscle. 

In  rabbits  and  cats  similar  changes  are  seen  in  the  circulation  after 
muscarine.  The  heart  is  slowed  or  brought  to  a  complete  standstill, 
the  blood  pressure  falls,  and  all  the  symptoms  produced  by  anaemia 
of  the  brain  may  follow,  but  the  animal  becomes  again  perfectly  nor- 
mal on  the  administration  of  small  quantities  of  atropiue.  The  fall  in 
blood-pressure  is  often  greater  than  is  accounted  for  by  the  slowing  of 
the  heart,  and  the  peripheral  vessels  are  extremely  congested.  This 
may  possibly  be  due  to  the  dilatation  of  the  vessels  which,  as  already 
stated,  accompanies  the  increased  activity  of  the  glands.  Pilocarpine 
differs  from  muscarine  here  in  several  particulars,  for  it  soon  depresses 
the  inhibitory  fibres  and  the  heart  regains  its  former  rhythm,  but  the 
cardiac  muscle  is  then  affected,  so  that  the  contractions  rapidly  be- 
come weaker  and  slower  again,  and  this  secondary  slowing  is  not  re- 
moved by  atropine ;  the  vaso-motor  centre  also  becomes  gradually 
weakened  by  large  doses,  so  that  the  blood  vessels  remain  somewhat 
dilated,  and  the  arterial  tension  remains  low  even  after  atropine. 

In  dogs,  the  stimulation  of  the  inhibitory  fibres  seems  sometimes  to 
be  entirely  absent  after  pilocarpine  and  muscarine,  and  in  man  this  is 
very  frequently  the  case.  Instead  of  a  slow  pulse  and  lessened  ten- 
sion in  the  arteries,  acceleration  and  increased  blood-pressure  are  then 
observed.  This  is  accompanied  in  man  by  marked  palpitation  and 
discomfort  in  the  region  of  the  heart  and  by  dilatation  of  the  skin 


316 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


vessels,  especially  of  those  of  the  face.  In  other  cases,  however,  the 
same  circulatory  disturbances  are  produced  as  in  the  cat  and  rabbit. 
(Fig.  29.)  No  explanation  of  the  acceleration  of  the  heart  has  been 


FIG.  29. 


B     A 


Tracings  of  the  movement  of  the  auricle  (upper)  and  ventricle  (lower)  of  the  dog  under  muscarine. 
During  contraction  the  levers  move  upwards  ;  during  relaxation  downwards.  A-B,  normal.  At  B, 
muscarine  was  injected  intravenously  and  at  C  it  began  to  act.  The  movements  of  the  ventricles  are 
slower  and  a  distinct  pause  is  seen  in  diastole.  The  contraction  is  less  complete,  while  the  heart 
relaxes  more  than  usual  during  diastole.  The  auricle  soon  comes  to  a  standstill  in  diastole.  Com- 
pare the  effects  of  stimulation  of  the  vagus  in  the  first  part  of  Fig  27,  page  289. 

offered,  but  Howell  has  found  acceleration  constantly  produced  by  mus- 
carine in  the  crab's  heart. 

In  embryo  hearts,  muscarine,  in  ordinary  quantities,  produces  no 
change  whatever  during  the  first  150  hours  of  life  (in  the  chick).  The 
explanation  of  this  phenomenon  is  that  the  inhibitory  nerves  have  not 
been  developed  at  this  stage,  and  after  their  development  is  complete, 
muscarine  acts  on  the  heart  as  in  the  adult.  The  absence  of  slowing 
in  some  of  the  invertebrates  may  be  due  to  a  similar  cause,  although 
this  does  not  held  good  for  the  crab,  in  which  there  is  a  well-defined 
inhibitory  apparatus. 

The  Respiratory  centre  is  not  acted  on  directly  by  small  quantities 
of  pilocarpine  and  muscarine.  But  the  changes  in  the  circulation 
lessen  the  amount  of  blood  passing  through  the  lungs,  and  the  contrac- 
tion of  the  bronchial  muscle  may  seriously  retard  the  movement  of 
the  air  and  thus  impair  the  aeration  of  the  blood.  This  bronchial 
constriction  may  be  the  explanation  of  the  O3dema  of  the  lungs  which  is 
often  observed  in  cats  and  rabbits  poisoned  with  the  members  of  this 
series,  and  which  has  also  occurred  in  fatal  poisoning  in  man.  Large 
quantities  of  pilocarpine  cause  a  tendency  to  convulsive  movements 
and  a  more  rapid  and  labored  respiration.  Eventually  the  respiration 
becomes  slow  and  weak  and  asphyxia  follows. 

It  has  been  found  that  pilocarpine  increases  the  Leucocytes  of  the 
blood,  and  this  is  generally  attributed  to  Iti=T  acting  on  tne  tissues 
which  form  leucocytes,  an  explanation  which  is  supported  by  the 


PILOCARPINE  AND  MUSCARINE.  317 

statement  of  Ruzicka,  that  the  Malpighiau  corpuscles  of  the  spleen  are 
increased  in  number  after  pilocarpine. 

The  Temperature  is  said  to  be  increased  by  pilocarpine,  although 
only  to  a  very  small  extent,  and  the  carbonic  acid  excretion  is  increased 
through  the  drug  increasing  the  activity  of  the  glands  and  other 
organs.  After  the  perspiration  is  fully  developed  the  internal  tem- 
perature is  generally  reduced,  especially  in  fever. 

Some  symptoms  occur  in  cases  of  poisoning  which  point  to  some 
action  of  the  alkaloids  on  the  Central  Nervous  System.  Thus  frogs 
develop  well-marked  convulsions,  and  even  in  the  higher  animals  and 
man  tremor  and  slight  convulsive  movements,  such  as  hiccough,  have 
been  observed.  In  the  later  stages  muscular  weakness  is  developed, 
and  the  slow  respiration  and  the  fall  in  blood-pressure  also  indicate  a 
central  action,  which  seems  to  be  confined  to  the  lower  parts  of  the 
nervous  system,  however,  for  consciousness  remains  little  altered. 
These  symptoms  may  be  complicated  by  marked  convulsions  which 
appear  to  be  due  to  the  anaemia  of  the  brain  and  do  not  denote  any 
direct  action  on  that  organ. 

Pilocarpine  and  muscarine,  while  resembling  each  other  in  general, 
present  some  points  of  difference,  which  are  of  the  greatest  importance 
as  regards  their  use  in  therapeutics.  Muscarine  has  practically  never 
been  introduced  into  medical  practice,  because,  while  its  action  on  the 
secretions  is  quite  equal  to  that  of  pilocarpine,  the  gastric  symptoms 
are  produced  much  more  readily  by  it.  It  is  also  a  very  much  more 
powerful  poison  than  pilocarpine,  and  is  much  less  easily  prepared  in 
pure  form. 

PREPARATIONS. 
(Muscarine  is  not  used  in  therapeutics.) 

Pilocarpus  (U.  S.  P.),  Jaborandi  Folia  (B.  P.),  the  dried  leaflets  of  Pilo- 
carpus  Jaborandi l  (and  of  P.  Selloanus,  U.  S.  P.). 

Fluidextractum  Pilocarpi  (U.  S.  P.),  £-2  c.c.  (8-30  mins.). 

Extractum  Jaborandi  Liquidum  (B.  P.),  5-15  mins. 

Tinctura  Jaborandi  (B.  P.),  £-1  fl.  dr. 

PILOCARPINE  HYDROCHLORIDUM  (U.  S.  P.)  (CUH16N2O2HC1),  the  hydro- 
chlorate  of  an  alkaloid  obtained  from  Pilocarpus,  forms  small,  white  crystals, 
odorless,  with  a  slight  bitter  taste,  deliquescent  in  the  air,  very  soluble  in  water 
and  alcohol.  0.003-0.03  G.  (^-%  gr.). 

PILOCARPINE  NITRAS  (U.  S.  P.,  B.  P.)  (C12H16N2O2HNO3),  the  nitrate  of 
an  alkaloid  obtained  from  Jaborandi  leaves,  forms  a  white  crystalline  powder, 
which  is  soluble  in  8-9  parts  of  cold  water,  and  is  freely  soluble  in  hot  alcohol. 

*Vi  gr- 

The  preparations  of  the  crude  drug  are  but  little  used,  as  they  vary  greatly 
in  their  activity  and  cause  nausea  and  vomiting  more  readily  than  the  alka- 
loidal  salts.  This  is  explained  by  the  fact  that  they  are  absorbed  more 
slowly  from  the  alimentary  canal,  and  therefore  have  longer  time  to  produce 
their  characteristic  effects  upon  it. 

Therapeutic  Uses  of  Pilocarpine.  —  Its  action  on  the  sweat  glands 
renders  pilocarpine  much  the  most  powerful  diaphoretic  in  the  gharma- 

1  Pilocarpus  Jaborandi  leaves  are  now  extremely  scarce  and  have  been  supplanted 
by  those  of  Pilocarpus  pinnatifolius  and  P.  microphyllus. 


318  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

copoeia,  and  it  is  used  internally  almost  exclusively  for  this  purpose. 
In  various  conditions  in  which  excess  of  fluid  accumulates  in  the  body, 
pilocarpine  may  be  exhibited  to  remove  it.  In  dropsy,  especially  that 
due  to  renal  disease,  a  few  injections  frequently  reduce  the  fluid  and 
remove  the  effects  of  the  accumulation,  although  they  do  not,  of  course, 
aftect  the  diseased  tissues  directly.  By  unburthening  the  blood  and 
tissues  of  their  excessive  fluid,  however,  pilocarpine  may  improve  the 
nutrition  of  the  kidney,  and  thereby  promote  its  recovery.  In  dropsy 
due  to  heart  disease  pilocarpine  must  be  used  with  caution,  owing  to 
its  exercising  a  depressant  action  on  the  circulation,  perhaps  on  the 
heart  itself.  In  some  other  pathological  exudations  pilocarpine  has  also 
been  advised,  as  in  pleural,  pericardia!  and  subretinal  effusion.  It  must 
be  remembered  that  after  the  diaphoresis  produced  by  pilocarpine  there 
usually  sets  in  a  period  of  depression,  weakness  and  languor,  and  this 
may  be  sufficient  to  counteract  the  improvement  obtained  by  the  re- 
moval of  the  fluid.  It  is  still  a  disputed  point  whether  pilocarpine 
possesses  any  advantage  as  a  diaphoretic  over  the  other  means  of  pro- 
ducing sweating,  such  as  hot  or  cold  packs.  Its  advocates  point  to 
the  fact  that  much  less  disturbance  of  the  patient  is  required,  and  that 
the  subsequent  depression  is  not  greater,  while  its  opponents  assert 
that  the  hot  or  cold  pack  produces  less  depression  and  is  not  accompa- 
nied by  the  unpleasant  salivation  and  occasional  nausea  of  pilocarpine. 
Accumulations  of  fluid  in  the  body  may  also  be  removed  by  way  of 
the  bowel  by  the  use  of  a  hydragogue  cathartic  or  preferably  a  saline 
purgative,  or  the  kidney  may  be  stimulated  to  special  activity  by  the 
use  of  such  diuretics  as  theobromine  and  caffeine.  The  last  method  of 
treatment  is  that  generally  preferred  as  it  induces  less  weakness  and 
depression  subsequently  than  either  of  the  others. 

In  uraemia  pilocarpine  sometimes  proves  of  great  benefit  if  exhibited 
earTy,  and  it  has  been  supposed  that  this  was  due  to  the  skin  taking 
up  the  renal  function  vicariously  and  eliminating  the  poison.  Some 
support  has  been  given  this  explanation  by  the  discovery  of  traces  of 
urea  in  the  perspiration  after  pilocarpine,  but  it  is  now  recognized  that 
the  urea  is  not  the  poisonous  principle  in  uraemia,  and  the  beneficial 
effects  are  probably  due  rather  to  the  removal  of  fluid  and  the  relief 
of  the  overstrained  circulation.  It  has  also  been  suggested  that  pilo- 
carpine acts  directly  on  the  kidney,  and  an  increase  in  the  urine  is  not 
infrequently  seen  after  several  injections  ;  but  this  is  to  be  ascribed 
rather  to  the  changes  in  the  circulation  following  the  removal  of  the 
fluid  than  to  any  direct  action  on  the  renal  epithelium,  for  which  there 
does  not  exist  any  satisfactory  experimental  evidence. 

Pilocarpine  has  been  used  in  a  number  of  fevers  and  in  diphtheria 
and  syphilis,  but  no  sufficient  evidence  of  improvement  in  those  con- 
ditions has  been  brought  forward. 

In  ophthalmic  surgery  pilocarpiue  has  been  employed  as  a  substi- 
tute for  physostigmine,  to  contract  the  pupil  and  reduce  the  intraocular 
pressure.  For  this  purpose  a  very  dilute  solution  of  the  salts  (2  per 
cent.)  may  be  used,  or  lamellae  of  gelatin  may  be  prescribed,  each  con- 


PILOCARPINE  AND  MUSCARINE.  319 

taining  i  mg.  (^i¥  gr.),  to  be  laid  on  the  conjunctiva.  The  contraction 
of  the  pupil  generally  attains  its  maximum  in  about  J-l  hour,  and 
passes  off  in  3-5  hours ;  it  is  generally  less  complete  and  of  shorter 
duration  than  that  seen  after  physostigmine.  Pilocarpine  first  in- 
creases and  then  lowers  the  intraocular  tension. 

I  n  various  diseases  of  the  ear,  pilocarpiue  has  been  used  with  good 
effects  m"some  cases,  ftut  it  is  quite  unknown  how  it  acts  here.  The 
conditions  in  which  it  is  of  service  are  various  forms  of  labyrinthine 
disease,  and  some  forms  of  effusion  into  the  tympanic  cavity. 

Pilocarpine  was  at  one  time  recommended  us  an  ecbolic  1  and  several 
cases  of  abortion  have  been  ascribed  to  its  use.  Further  experience 
has  led  to  the  conclusion,  however,  that  if  it  possesses  any  action 
whatsoever  on  the  pregnant  uterus  it  only  does  so  when  administered 
in  quantities  which  produce  undesirable  secondary  symptoms. 

Pilocarpine  is  frequently  prescribed  in  lotions  for  the  hair,  and  a 
renewed  growth  of  the  hair  has  been  frequen tly  seen  _in  alopecia  treated 
iiithis  way.     This  has  been  explained  by  its  action  on  the  glands  of 
tlu>  skin,  increasing  the  moisture  of  the  scalp  and  improving  its  circu- 
lation and  nutrition,  but  Tappeiner  found  that  the  local  application    I 
of  pilocarpine  to  the  skin  produced  no  increase  in  the  secretion  of  the,/ 
glands. 

In  cases  of  atropine  poisoning,  large  doses  of  pilocarpine  have  been 
ordered  with  alleged  good  results.  In  animal  experiments,  however, 
the  quantity  of  pilocarpine  necessary  to  antagonize  even  small  doses  of 
atropine  has  been  found  to  be  so  large  that  there  is  little  reason  to 
hope  for  improvement  from  its  administration  in  poisoning  in  man, 
especially  as  the  action  of  atropine  on  the  central  nervous  system  is 
not  antagonized  by  pilocarpine.  In  poisoning  from  pilocarpine  or 
muscarine  small  quantities  of  atropine  are  the  antidote  recommended 
alike  by  pharmacological  experiment  and  by  clinical  experience. 

Muscarine  Intoxication.  —  In  Siberia  the  Agaricus  muscarius  is  used 
to  form  an  intoxicating  beverage.  The  symptoms  produced  are  hilarity 
and  jollity,  and  the  victims  declare  themselves  to  be  more  capable 
of  fatiguing  exertions  than  they  would  be  without  the  preparation. 
Eventually  giddiness  and  somnolence  are  produced,  and  after  large 
quantities  vomiting  and  convulsive"  attacks  may  follow  and  eventually 
prove  fatal.  The  exhilarating  effects  are  probably  due  to  the  presence 
of  a  poison  discovered  by  Harmsen  and  not  to  the  muscarine.  This 
new  poison  seems  to  play  a  role  at  least  as  important  as  that  of  mus- 
carine in  cases  of  amanita  poisoning ;  it  is  not  antagonized  by  atro- 
pine, and  its  chemical  nature  is  unknown. 

1  An  ecbolic  is  a  drug  used  to  evacuate  the  contents  of  the  uterus. 


320  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

BIBLIOGRAPHY.1 

Muscarine. 

Schmiedeberg  u.  Koppe.     Das  Muscarin.     Leipzig,  1869. 

Krenchel.     Arch.  f.  Ophthalm.,  Bd.  xx.,  p.  135. 

Ringer.     Journ.  of  Phys.,  iii.,  p.  115. 

Gaskell.     Phil.  Trans.  Roy.  Soc.,  1882.     Journ.  of  Physiol.,  iii.,  iv.,  viii. 

Dixon  and  Brodie.     Journ.  of  Phys.,  xxix.,  p.  155. 

Harmsen.     Arch.  f.  exp.  Path.  u.  Pharm.,  1.,  p.  361. 

NolhnageL     Berichte  der  Berl.  Chern.  Gesellsch.,  1893,  i.,  p.  801. 

Schultz.     Arch.  f.  Anat.  u.  Phys.,  1898,  p.  73. 

Pilocarpine. 

Langley.  Journ.  of  Anatomy  and  Physiol.,  x.,  p.  187.  Journ.  of  Physiol.,  i.,  iii. 
Cf.  Nicotine. 

Luchsinger.    Pfliiger's  Archiv,  xv.,  p.  482  ;  xviii.,  p.  501. 

Lewin.     Charite-annalen,  v.,  p.  489. 

Ringer  and  Murrell.     Journ.  of  Physiol.,  ii.,  p.  135  ;  Practitioner,  xxvi.,  p.  5. 

Albertoni.     Arch.  f.  exp.  Path.  u.  Pharm.,  xi.,  p.  415. 

Nawroeki.     Centralbl.  f.  d.  med.  Wissensch.,  1878,  p.  97. 

Harnack  u.  Meyer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xii.,  p.  366. 

Frank  and  Voit.     Ztschr.  f.  Biol.,  xliv.,  p.  111. 

Schlegel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xx.,  p.  271. 

Schi/.     Archiv  f.  Verdauungskrh.,  vi.,  p.  107. 

Marshall.     Journ.  of  Physiol.,  xxxi.,  p.  120. 

XV.     PHYSOSTIGMINE. 

Physostigmine  or  Eserine  is  the  chief  alkaloid  of  the  Calabar  bean, 
or  Ordeal  bean  (Physostigma  venenosum),  which  grows  in  Western 
Africa  and  was  employed  there  by  the  natives  in  the  trials  by  ordeal 
for  witchcraft.  Either  physostigmine  itself,  or  a  nearly  allied  alkaloid, 
occurs  also  in  the  Kali  or  Cali  nuts,  the  seeds  of  Mucuna  urens.  The 
constitution  of  physostigmine  (C15H21N3O2)  is  still  unknown.  Two 
other  alkaloids  have  been  found  in  the  extract  of  the  Calabar  bean  and 
are  probably  products  of  the  decomposition  of  physostigmine,  which  is 
a  very  unstable  body.  These  are  Calabarine,  which  resembles  strych- 
nine in  its  effects,  and  Eseridine,  which  acts  in  the  same  way  as  physo- 
stigmine, but  is  much  less  poisonous. 

Physostigmine  produces  a  number  of  symptoms  resembling  those  of 
muscarine  and  pilocarpine  poisoning,  and  many  authors  describe  all 
three  together,  but  it  departs  in  certain  points  from  the  type  of  these 
two  drugs,  and  according  to  one  theory  acts  upon  a  different  set  of 
tissues. 

Symptoms. — The  symptoms  of  poisoning  vary  but  little  in  different 
animals ;  in  the  dog  and  rabbit  the  first  results  of  a  large  dose  of 
physostigmine  are  weakness  in  the  voluntary  movements  and  a  curious 
tremor  and  muscular  twitching,  beginning  in  the  hind  legs,  but  soon 
extending  over  the  whole  body.  The  animal  falls  on  one  side  and  can 
not  raise  itself  again,  although  it  makes  efforts  to  do  so  when  touched. 

aThe  literature  of  muscarine  and  pilocarpine  is  so  mixed  with  that  of  atropine,  nico- 
tine and  physostigmine,  that  a  complete  list  would  involve  numerous  repetitions.  I 
must,  therefore,  refer  those  interested  to  the  bibliography  given  under  those  groups, 
and  shall  mention  here  only  the  papers  which  deal  very  largely  with  muscarine  and 
pilocarpine. 


PHYSOSTIGMINE. 


321 


The  saliva  and  tears  are  increased,  the  bowel  is  often  evacuated  and 
in  the  dog  vomiting  is  common.-  The  respiration  is  at  first  rapid 
and  deep,  and  later  slow  and  dyspnceic,  the  heart  is  weak  and  slow, 
and  the  pupil  is  contracted  to  a  small  point.  These  symptoms  become 
more  marked  as  more  of  the  poison  reaches  the  blood,  until  the  respira- 
tion ceases.  In  cats  these  symptoms  of  depression  and  paralysis  are  pre- 
ceded by  a  stage  of  increased  movement  and  evident  anxiety,  but  the 
later  symptoms  resemble  those  in  the  dog.  In  man  physostigmine  elicits 
practically  the  same  results  as  in  the  dog,  vomiting  and  pain  in  the 
stomach  region,  dyspnoea,  giddiness  and  muscular  weakness,  contrac- 
tion of  the  pupil,  salivation  and  perspiration.  The  heart  is  slow, 
muscular  twitching  may  be  present  and  complete  collapse  follows.  In 
frogs  the  voluntary  movements  disappear  soon  after  the  injection  of 
physostigmine,  the  respiration  ceases,  and  last  of  all  the  reflexes  are 
paralyzed. 

Action.  —  Many  of  these  symptoms  evidently  arise  from  depression 
of  the  Central  Nervous  System,  and  the  cause  of  death  is  the  failure  of 
the  respiration  from  paralysis  of  the  medullary  centre.  Some  doubt 
exists  as  to  what  parts  of  the  nervous  system  first  undergo  depression. 
Thus  according  to  Harnack  and  Witkowsky,  the  higher  centres  are 
weakened  earlier  than  the  lower  ones,  but  in  man  at  any  rate,  the 
consciousness  remains  unimpaired  after  grave  derangement  of  the 
respiration  has  manifested  itself  and  after  the  muscular  power  is  con- 
siderably depressed.  This  would  indicate  that  some  of  the  higher 
cerebral  areas  preserve  their  functions  after  others  have  been  weakened, 
and  several  authors  have  therefore  maintained  that  the  depression 
commences  in  the  cord  and  medulla  oblongata,  and  only  spreads  to  the 
cerebrum  after  large  doses. 

Another  unsettled  question  is  whether  the  stage  of  depression  is  preceded 
by  one  of  direct  stimulation  of  the  nervous  centres.  Some  symptoms  un- 
doubtedly point  to  an  increase  in  their  irritability  ;  for  example  the  increased 
respiratory  movements,  and  to  some  extent  the  changes  in  the  blood-pressure 
can  scarcely  be  explained  save  by  stimulation,  direct  or  indirect. 

Further  evidence  of  the  stimulant  action  of  physostigmine  on  the  central 
nervous  system  has  been  offered  by  its  effects  in  epileptics,  in  whom  the 
number  and  intensity  of  the  seizures  are  increased  by  its  use.  Guinea- 
pigs  rendered  epileptic  by  operative  procedures  are  also  said  to  be  more 
frequently  attacked  when  physostigmine  is  exhibited,  and  even  in  the  dog 
epileptiform  convulsions  occur  occasionally,  while  in  the  cat  a  stage  of 
excitement  is  a  regular  precursor  of  the  depression.  These  symptoms  have 
been  explained  by  some  writers  as  due  to  stimulation  of  the  central  nervous 
system,  but,  on  the  other  hand,  may  be  due  to  the  peripheral  effects  of  the 
poison,  such  as  the  constriction  of  the  air  passages  by  contraction  of  the 
bronchial  muscles.  The  question  as  to  whether  any  general  stimulation  of 
the  central  nervous  system  occurs  in  physostigmine  poisoning  must  be  left 
open  for  the  present. 

The  muscular  twitching  seems  to  be  entirely  independent  of  the 
central  nervous  system,  for  it  is  not  prevented  by  division  of  the  motor 
nerves.     This  symptom  is  not  marked  in  frogs,  but  may  be  so  devel- 
oped in  mammals  as  to  simulate  convulsions,  and  is  due  to  stimulation 
21 


322  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

of  the  nerve  terminations  in  the  muscles,  for  it  is  prevented  by  curara, 
which  paralyzes  these.  The  antagonism  between  these  two  alkaloids  is 
mutual,  for  the  paralysis  of  the  motor  nerves  induced  by  curara  may 
be  removed  by  physostigmine  applied  in  somewhat  large  doses,  and 
animals  may  thus  be  recovered  from  quantities  of  curara  which  would 
otherwise  prove  fatal. 

The  Respiration  is  at  first  somewhat  accelerated  and  then  becomes 
slow  and  weak.  The  preliminary  acceleration  was  explained  by 
Bezold  and  Gotz  as  due  to  stimulation  of  the  sensory  terminations  in 
the  lungs,  while  others  regard  it  as  evidence  of  central  stimulation. 
The  subsequent  weakness  and  slowness  of  the  breathing  is  undoubtedly 
of  central  origin,  and  death  follows  from  the  failure  of  the  respiratory 
centre. 

The  changes  in  the  Circulation  require  further  investigation. 
Small  doses  slow  the  pulse  and  increase  the  blood-pressure,  while 
larger  are  followed  by  greater  slowing  of  the  heart  and  a  fall  in 
the  blood-pressure.  The  slowness  of  the  pulse  is  due  to  the  poison 
acting  on  the  heart  directly  and  not  to  any  inhibitory  interference,  for 
it  occurs  after  large  quantities  of  atropine.  The  action  of  physostig- 
mine on  the  inhibitory  nerves  has  never  been  satisfactorily  decided,  for 
according  to  some  authors  they  are  unaffected,  while  others  assert  that 
their  irritability  is  increased,  and  Arnstein  and  Sutschinsky  even  state 
that  the  paralyzing  effects  of  atropine  may  be  removed  by  it.  The  con- 
tractions of  the  mammalian  heart  are  sometimes  said  to  be  strengthened 
by  physostigmine,  but  this  is  erroneous ;  the  increased  amplitude  of 
the  movements  mentioned  by  Hedbom  may  be  due  to  the  slow 
rhythm. 

The  increased  blood-pressure  has  also  been  the  subject  of  some  dis- 
cussion. It  seems  independent,  in  part  at  least,  of  the  vaso-motor 
centre,  for  it  is  not  prevented  by  section  of  the  spinal  cord  or  of  the 
splanchnic  nerves,  operations  which  prevent  impulses  from  the  centre 
reaching  the  vessels.  It  may  be  partly  due  to  the  powerful  contrac-  £ 
|  tion  of  the  intestines  expelling  the  blood  from  the  mesenteric  area,  or  I 

*  to  direct  action  on  the  muscular   coats  of  the  arterioles  causing  con-  | 
I  traction  and  thus  narrowing  their  calibre,  or  perhaps  to  both  of  these,  \ 

*  along  with  some  increase  in  the  activity  of  the  vaso-motor  centre. 

The  frog's  heart  beats  more  slowly  after  physostigmine,  but  here 
the  individual  contractions  are  said  to  be  strengthened  and  prolonged, 
and  there  is  definite  evidence  of  stimulation  of  the  heart  muscle,  which 
is  not  seen  in  mammals.  If  the  vagus  be  stimulated  in  the  frog  after 
physostigmine,  it  produces  slowing  but  no  complete  standstill  of  the 
heart,  because  the  irritability  of  the  muscle  is  so  much  augmented  that 
the  inhibitory  apparatus  can  no  longer  entirely  control  it.  It  has  been 
supposed  that  physostigmine  depresses  the  endings  of  the  inhibitory 
nerves,  but  this  has  been  shown  to  be  incorrect.  If  such  a  poison  as 
muscarine  produces  complete  standstill,  physostigmine  removes  it,  not 
by  inducing  depression  of  the  inhibitory  apparatus,  but  by  increasing 
the  irritability  of  the  muscle. 


PHYSOSTIGMINE. 


323 


The  following  experiment,  which  is  mainly  a  repetition  of  one  devised  by 
Harnack,  may  serve  to  show  the  relationship  between  the  effects  of  a  whole 
series  of  poisons,  which  generally  present  some  difficulties  to  the  student. 
A  frog,  with  brain  and  spinal  cord  destroyed,  is  stretched  on  a  board,  and 
its  heart  is  exposed  by  the  removal  of  a  triangular  piece  of  skin  and  division 
of  the  sternum.  The  poisons  are  then  applied  in  succession  by  injecting 
them  into  the  lymph  sac,  and  the  vagus  may  be  exposed  and  placed  on  elec- 
trodes. 

The  injection  of  nicotine  causes  slowing  of  the  heart  (Fig.  30,  N),  followed  by 
a  return  to  the  normal  rhythm,  after  which  vagus  stimulation  has  no  effect, 
while  stimulation  of  the  sinus  still  slows  the  heart.  (Nicotine  first  stimu- 
lates and  then  paralyzes  the  ganglia  on  the  course  of  the  inhibitory  fibres.) 
Muscarine  now  brings  the  heart  to  a  standstill  (Fig.  30,  M),  through  stimu- 
lation of  the  terminations  of  the  inhibitory  fibres  ia  the  muscle.  Physostig- 
mine restores  the  heart  to  feeble  rhythmic  contractions  (Fig.  30,  P),  through 
stimulation  of  the  muscular  fibres,  which  leads  to  a  partial  loss  of  control 
by  the  inhibitory  apparatus.  Copper  salts  or  other  muscular  depressants 
cause  a  return  of  the  standstill  (Fig.  30,  (7),  through  neutralizing  the  stimu- 
lant action  of  physostigmine,  and  thus  allowing  the  stimulated  inhibitory 
endings  to  regain  control.  Atropine  finally  induces  an  almost  complete 
return  to  the  normal  rhythm  (Fig.  30,  A)  by  paralyzing  the  terminations  of 
the  inhibitory  nerves  and  thus  removing  the  effects  of  the  muscarine. 

Here  there  is  distinct  evidence  of  an  increase  in  the  irritability  of  the  car- 
diac muscle  of  the  frog  after  physostigmine,  and  this  is  difficult  to  reconcile 
with  the  slow  pulsation  generally  seen  when  physostigmine  is  given  alone. 
In  the  mammalian  heart  no  such  evidence  of  an  increase  in  the  muscular 
irritability  has  been  adduced,  and  the  vagus  arrests  it  as  easily  as  before  the 
administration  of  the  poison  ;  according  to  some  investigators  even  more 
easily. 

FIG.  30. 


Tracing  of  the  movements  of  the  frog's  ventricle.    During  systole  the  lever  makes  an  up-stroke. 
Z.  Normal,    N.  After  nicotine     M.  After  muscarine.     P.  After  physostigmine.     C.  After  a  copper 


Bait.    A.  After  atropine.     (See  text.) 


Physostigmine  produces  powerful  contractions  of  the  Stomach  and 
Intestine  exactly  resembling  those   elicited    by  muscarine  and  pilo- 


324  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

carpine.  It  differs  from  these,  however,  in  causing  these  move- 
ments after  small  quantities  of  atropine,  while  larger  doses  of  atropine 
again  stop  the  contractions  set  up  by  physostigmine. 

The  Secretions  are  also  increased  by  physostigmine  as  by  pilocarpine 
and  muscarine,  and  here  again  small  quantities  of  atropine  do  not 
prevent  the  action,  while  larger  quantities  arrest  it.  Thus,  the  saliva, 
the  tears,  the  perspiration,  the  mucous  secretions  and  the  pancreatic 
juice  are  all  augmented  by  physostigmine. 

Besides  the  intestine  and  stomach,  a  number  of  other  muscular 
organs  are  thrown  into  contraction  by  physostigmine  —  ureter,  bladder, 
uterus  and  bronchial  muscle.  The  Intraocular  Muscles  also  undergo 
contraction,  and  their  movements  under  physostigmine  have  been  the 
subject  of  a  large  number  of  investigations  and  of  a  good  deal  of  con- 
troversy. The  pupil  contracts  when  physostigmine  is  employed  either 
locally  or  internally,  and  this  contraction  may  be  lessened  by  the  sub- 
sequent application  of  atropine,  but  is  not  altogether  removed  except 
by  large  quantities.  On  the  other  hand,  the  dilatation  of  the  pupil 
produced  by  small  quantities  of  atropine  may  be  diminished  by  physos- 
tigmine, but  the  resulting  contraction  is  much  less  than  that  caused 
by  physostigmine  applied  to  the  normal  eye.  The  ciliary  muscle  is 
acted  on  in  the  same  way  as  the  pupil,  so  that  the  eye  becomes  accom- 
modated for  near  distance,  and  atropine  induces  the  same  modifica- 
tions., The  effects  of  physostigmine,  then,  on  the  intestine,  secretory 
organs,  pupil  and  ciliary  muscle  are  strictly  analogous,  and  are  gen- 
erally attributed  to  the  alkaloid  stimulating  the  terminations  of  the 
nerves  in  these  organs.1  It  therefore  resembles  pilocarpine  and  mus- 
carine but  its  antagonism  to  atropine  is  much  more  complete,  and  a 
renewal  of  the  secretion  or  contraction  after  atropine  can  be  elicited 
much  more  easily  by  physostigmine  than  by  muscarine  or  pilocarpine. 
The  intraocular  pressure  is  considerably  reduced  by  the  application  of 
physostigmine  to  the  eye  and  this  has  generally  been  attributed  to  the 
contraction  of  the  pupil  facilitating  the  escape  of  the  fluid  by  allowing 
it  freer  access  to  the  spaces  of  Fontana.  But  the  latest  writer  on  the 
subject,  Gronholm,  states  that  it  is  due  to  a  contraction  of  the  intra- 
ocular vessels,  which  lessens  the  secretion. 

Physostigmine  is  Excreted  in  the  urine  mainly,  appearing  in  it  a  few 
minutes  after  its  injection.  It  has  also  been  found  in  the  saliva  and  bile. 

The  symptoms  of  poisoning  with  Calabar  bean  are  identical  with 
those  caused  by  physostigmine,  except  when  an  old  preparation  con- 
taining calabarine  is  used,  when  some  stimulation  of  the  spinal  cord 
may  be  induced. 

PREPARATIONS. 

Physostigma  (U.  S.  P.),  Physostigmatis  Semina  (B.  P.),  Calabar  or  Or- 
deal bean,  the  seeds  of  Physostigma  venenosum. 

Extractum  Physostigmatis  (U.  S.  P.,  B.  P.),  0.015-0.06  G.  (J-l  gr.). 

Another  theory  formulated  by  Harnack  Js  Jhat,  while  atropine  acts  on  the  termina- 
tions of  the  nerves  in  these  organs,  physostigmine  acts  upon  the  organs  themselves — 
on  the  secretory  cells  of  the  glands  and  on  the  muscle  fibres  of  the  intestine,  pupil,  etc. 


PHYSOSTIGMINE.  325 

Tinctura  Physostigmatis  (U.  S.  P.),  1-3  c.c.  (15-45  mins.). 
PHYSOSTIGMINE  SALICYLAS,  eserine  salicylate  (U.  S.  P.),  0.003  G.  (2V  gr-)- 
PHYSOSTIGMINJE  SULPHAS,  eserine  sulphate  (U.  S.  P.,  B.  P.),  0.001-0.003 


Lamellse  Physostigminse  (B.  P.),  each  containing  ^Q-Q  gr.  of  physostigmine 
sulphate. 

The  sulphate  and  salicylate  of  physostigmine  are  colorless  or  faintly  yel- 
low crystals,  without  odor,  but  possessing  a  bitter  taste.  The  sulphate  is 
deliquescent  in  the  air  and  is  very  soluble  in  both  alcohol  and  water.  The 
salicylate  is  not  deliquescent,  has  usually  a  slight  acid  reaction,  and  is  solu- 
ble in  150  parts  of  cold,  or  30  parts  of  boiling  water.  Both  salts  undergo 
decomposition  when  kept  in  solution  and  then  assume  a  reddish-brown 
color  ;  the  addition  of  boric  or  sulphurous  acid  to  the  solution  is  said  to 
retard  this  decomposition.  Preparations  of  the  crude  drug  also  lose  their 
activity  when  kept  for  some  time,  but  these  are  very  seldom  prescribed. 

Therapeutic  Uses.  —  Physostigmine  has  been  used  for  its  depressant 
action  on  the  central  nervous  system  in  cases  of  abnormal  excitability 
of  the  cerebral  cortex.  In  epilepsy  and  chorea  it  has  received  a  fairly 
extensive  trial,  but  has  proved  of  little  or  no  service  in  most  cases, 
and  is  positively  deleterious  in  some.  The  results  in  the  treatment  with 
it  of  other  diseases  of  the  central  nervous  system,  such  as  tetanus,  have 
been  no  more  favorable,  so  that  it  has  fallen  into  disuse. 

In  recent  years  physostigmine  has  been  given  in  pills  or  hypo- 
dermically  in  cases  of  atony  of  the  intestine  leading  to  tym- 
panitis and  meteorism.  But  it  is  chiefly  used  for  its  action  on  the 
intraocular  muscles  and  tension.  For  this  purpose  a  solution  of  J-l 
per  cent,  is  dropped  in  the  eye,  2-4  drops  at  a  time,  or  small  discs  of 
gelatin  impregnated  with  the  alkaloid  may  be  applied  to  the  conjunc- 
tiva (B.  P.).  The  pupil  begins  to  contract  in  5-15  minutes,  and  at- 
tains its  smallest  size  in  half  an  hour.  It  remains  contracted  12-14 
hours,  and  according  to  some  observers  a  difference  in  the  size  of  the 
two  pupils  may  be  made  out  for  several  days.  The  ciliary  muscle 
contracts  along  with  the  iris,  and  the  eye  becomes  accommodated 
for  short  distances.  This  action  on  the  accommodation  passes  off  in 
2-4  hours,  but  the  sight  is  often  rendered  indistinct  for  some  hours 
longer  by  alternate  contraction  and  relaxation  of  the  ciliary  muscle. 
The  action  of  physostigmine  on  the  eye  differs  from  that  of  muscarine 
for  the  former  acts  more  on  the  pupil,  the  latter  on  the  ciliary  muscle, 
and  the  pupil  is  often  contracted  by  physostigmine  while  the  accom- 
modation is  practically  unchanged.  The  intraocular  pressure  is  some- 
what increased  at  first  and  subsequently  sinks.  Its  action  in  narrow- 
ing the  pupil  after  atropine  has  been  made  use  of  to  remove  the  dilation 
produced  so  frequently  in  ophthalmic  surgery,  but  some  newer  tropeines, 
which  produce  a  shorter  mydriasis  than  atropine,  have  almost  driven 
it  from  this  field.  It  antagonizes  the  dilatation  of  the  pupil  after 
homatropine  and  cocaine  much  more  successfully  than  that  due  to 
atropine.  It  has  also  been  used  in  cases  of  synechia  (attachment  of 
the  iris  to  the  lens)  alternately  with  atropine.  The  alternate  contrac- 
tion and  dilatation  of  the  pupil  would,  it  was  hoped,  break  down  the 
attachment,  but  the  condition  is  now  generally  treated  by  operation. 


326  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Physostigmine  is  now  chiefly  employed  to  reduce  the  intraocular 
pressure  in  glaucoma. 

Physostigmine  Poisoning  has  occurred  only  from  eating  the  bean  as 
yet,  and  is  to  be  treated  by  the  usual  methods  of  evacuation  of  the 
stomach  and  other  general  measures.  It  has  been  found  by  Fraser 
that  atropine  acts  as  an  antidote  to  physostigmine  in  animals,  and  it 
might  be  tried  in  cases  of  poisoning.  The  foil  dose  of  atropine  is 
required. 

BIBLIOGRAPHY. 

Fraser.  Edinburgh  Medical  Journal,  ix.,  p.  36,  1864.  Journal  of  Anat.  and 
Physiol.,  1867,  p.  323.  Practitioner,  iv.,  p.  65. 

Bezoldu.  Gotz.     Centralbl.  f.  d.  med.  Wissenschaft,  1867,  p.  241. 

Arnsteinu.  Sustschinsky.    Untersucli.  a.  d.  physiol.  Laborator.  zu  Wiirzburg,  ii.,  p.  81. 

Rogoiu.     Ztschr.  f.  rationelle  Heilkunde,  xxix.,  p.  1. 

Heidenhain.     Pfl tiger's  Arch.  f.  Physiol.,  v.,  p.  309. 

Laschkewich.     Virchow's  Archiv,  xxxv.,  p.  291. 

Harnack  u.   Witkowski.     Arch.  f.  exp.  Path.  u.  Pharm.,  v.,  p.  401. 

Harnack  u.  Meyer.     Ibid.,  xii.,  p.  366. 

Turtschaninow.     Ibid.,  xxxiv.,  p.  208. 

Schweder.     Inaugural  Dissertat.,  Dorpat,  1889. 

Hedbom.     Skandinav.  Arch.  f.  Physiol.,  viii. ,  p.  209. 

Schultz.     Arch.  f.  [Anat.  u.]  Phys.,  1898,  p.  66. 

Rothberger.     Pfl  tiger's  Arch.,  Ixxxvii.,  p.  117. 

Grilnholm.     Arch.  f.  Ophthalmol.,  xlix.,  p.  620. 

Resume.  —  A  number  of  the  groups  of  alkaloids  discussed  up  to  this 
point  act  on  the  same  peripheral  organs  and  generally  present  some  diffi- 
culty to  the  student,  so  that  a  few  general  remarks  regarding  them  may 
be  of  service.  These  drugs  acts  at  two  distinct  points — the  peripheral 
ganglia  and  the  terminations  of  the  nerves  in  the  muscular  or  glandu- 
lar tissues.  Xicotine,  curara  and  coniine  affect  the  ganglia  (Fig.  31, 
N) ;  muscarine,  pilocarpine,  physostigmine  and  atropine  the  termina- 
tions in  the  organs  (J/,  Fig.  31).  Curara,  coniine  and  atropine  are 
purely  depressant  in  their  peripheral  action  ;  nicotine  is  first  stimulant 
and  subsequently  depressant,  while  muscarine,  pilocarpine  and  physos- 
tigmine are  practically  purely  stimulant.  The  action  on  the  ganglia  is 
quite  independent  of  that  on  the  nerve  ends,  and  either  may  be  stimu- 
lated or  depressed  after  the  others  have  been  paralyzed.  If,  however, 
the  nerve  ends  be  paralyzed  (Fig.  31,  2)  as  by  atropine,  changes  in  the 
ganglia  will  have  no  apparent  effect,  as  the  impulses  arising  from  their 
stimulation  are  blocked  in  the  nerve  ends,  and,  on  the  other  hand,  their 
paralysis  does  not  cause  any  further  retardation  of  centrifugal  im- 
pulses which  are  completely  blocked  already.  After  paralysis  of  the 
ganglia  (Fig.  31,  3)  the  stimulation  of  the  nerve  ends  is  followed  by 
the  usual  symptoms,  because  the  impulses  pass  from  the  nerve  ends  to 
the  epithelium  directly  without  the  intervention  of  the  ganglia.  Thus 
muscarine,  pilocarpine  and  physostigmine  act  after  the  paralysis  of  the 
ganglia  by  nicotine  or  coniine.  If  the  ganglia  be  paralyzed  first,  the 
paralysis  of  the  nerve  ends  by  atropine  is  followed  by  no  change  unless 
the  latter  have  been  in  a  state  of  activity.  While  it  is  universally 
acknowledged  that  atropine  arrests  the  action  of  muscarine  and  pilo- 
carpine by  paralyzing  the  points  at  which  these  unfold  their  action, 


RESUME, 


327 


FIG.  31. 


the  subsequent  stimulation  of  the  paralyzed  terminations  by  further 
administrations  of  muscarine  or  pilocarpine  is  by  no  means  so  generally 
believed.  The  statement  that  a  paralyzed  organ  cannot  be  further 
stimulated  seems  to  have  assumed  almost  the  authority  of  a  theological 
dogma,  although  numerous  points  not  only  in  the  peripheral  action  of 
these  drugs,  but  also  in  that  of  others  on  the  central  nervous  system 
cannot  be  easily  explained  ex- 
cept on  the  opposite  assumption. 
Some  of  the  difficulties  confront- 
ing the  advocates  of  this  theory 
have  been  already  mentioned, 
and  others  will  be  met  with  in 
the  course  of  this  work.  If  it  be 
granted  that  a  paralyzed  tissue 
may  be  restored  by  the  action  of 
stimulant  drugs,  the  action  of  the 
foregoing  alkaloids  is  much  sim- 
plified. Thus  atropine  paralyzes 
the  nerve  terminations,  but  these 
may  be  restored  to  activity  by 
very  large  quantities  of  muscarine 
or  pilocarpine,  unless  the  quan- 
tity of  atropine  given  has  been 
too  large.  The  quantity  of 
physostigmine  required  to  re- 
store them  is  much  smaller  than 
that  of  pilocarpine,  and  its  ap- 
plication is  therefore  much  more 
successful  in  reinstating  the  con- 
dition of  active  stimulation. 
These  differences  between  pilo- 
carpine and  physostigmine  may 
perhaps  be  explained  on  the 
analogy  of  the  chemical  theory 
of  mass  action  ;  the  "  affinity  " 
of  atropine  for  the  nerve  endings 
is  then  greater  than  that  of  any 
of  the  other  alkaloids  under  dis- 
cussion, that  of  physostigmine 
next,  and  that  of  pilocarpine 
and  muscariue  least.  The  last 
mentioned  are  therefore  expelled  from  their  combination  with  the 
protoplasm  by  very  small  quantities  of  atropine,  and  have  to  be  given 
in  very  large  quantities  to  remove  the  atropine  from  its  combination. 
On  the  other  hand,  the  attraction  of  physostigmine  for  the  nerve  ends 
seems  much  greater ;  larger  quantities  of  atropine  are  required  to  dis- 
place it,  and  smaller  quantities  of  physostigmine  restore  the  activity 
of  the  nerve  ends. 


Diagram  of  a  nerve  fibre  supplying  a  secretory 
gland.  X,  terminations  of  the  cerebrospinal 
nerve  round  a  ganglion  cell.  J/  the  termina- 
tions in  the  epithelium  of  the  sympathetic  fibre 
from  the  ganglion  cell.  In  1  the  connection  be- 
tween the  central  nervous  system  and  the  secre- 
tory cells  is  intact,  and  secretion  may  be  induced 
by  impulses  from  the  centres,  by  stimulation  at 
N  or  at  M.  In  2  all  connection  between  the 
nerve  and  the  epithelium  is  broken  off,  and  se- 
cretion can  be  induced  only  by  stimulation  of 
the  secretory  cells  or  by  restoring  the  connec- 
tion. In  3  the  connection  is  interrupted  in  the 
ganglion,  and  secretion  can  be  caused  only  by 
drugs  acting  directly  on  the  epithelium  of  on 
the  terminations  J/. 


328  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


XVI.     ACONITINE. 

This  series  embraces  a  number  of  alkaloids,  which  resemble  each 
other  so  closely  in  their  chemical  and  pharmacological  properties  as  to 
allow  of  their  being  treated  together.  Some  of  them  which  were 
formerly  believed  to  be  perfectly  distinct,  are  now  said  to  be  identical, 
and  it  is  not  improbable  that  future  investigation  will  still  further 
reduce  the  numbers  of  the  group. 

These  alkaloids  are  found  in  a  number  of  species  of  the  Aconitum 
genus,  the  best  known  of  which  are  Aconitum  Napellus  containing 
Aeonitine  (C^H^NO^  or  C34H47NOU),  Aconitum  ferox,  Pseudaconitine 
(C36H49NO12),  and  Aconitum  Japonicum,  Japaconitine  (C34H49NOn). 

When  aqueous  solutions  of  these  alkaloids  are  heated,  they  are 
broken  up  into  one  or  more  acids  and  simpler  bases,  so  that  they  may 
be  classed  with  those  of  the  atropine  and  cocaine  series,  which  are 
similarly  decomposed.  Aeonitine  forms  acetic  acid  and  Benzaconine 
(or  picroaconitine),  which  may  again  be  broken  down  into  benzoic  acid 
and  Aconine,  so  that  aconitine  is  acetyl-benzoyl-aconine.  Pseudaconi- 
tine forms  Pseudaconine,  and  Japaconitine  Japaconine  in  the  same  way. 
These  decomposition  products  are  found  in  the  plant  and  in  the  ordi- 
nary preparations,  and  in  many  of  the  commercial  "  aconi tines " 
benzaconine  and  aconine  occur  in  varying  proportions,  so  that  their 
toxicity  varies  very  considerably. 

Another  alkaloid  which  resembles  aconitine  closely  in  its  pharma- 
cological action,  but  which  is  less  known,  is  Delphinine.  It  is  found 
in  stavesacre  (Dephinium  Staphisagria),  along  with  a  number  of  other 
bases,  which  may  be  the  products  of  its  decomposition. 

The  symptoms  caused  by  aconitine,  pseudaconitine,  Japaconitine,  and 
delphinine  are  very  similar,  differing  mainly  in  degree  and  not  in  kind. 
Pseudaconitine  is  more  poisonous  than  Japaconitine  which  in  turn  is 
slightly  more  active  than  aconitine.  Delphinine  is  much  less  poi- 
sonous. 

Symptoms.  —  After  very  large  quantities  of  aconitine  death  may  re- 
sult instantaneously,  apparently  from  simultaneous  failure  of  the  heart 
and  central  nervous  system. 

If  smaller  quantities  be  swallowed  there  is  noted,  after  the  ordinary 
bitter  taste  of  the  alkaloid,  a  feeling  of  warmth  in  the  mouth  and 
throat,  which,  agreeable  at  first,  soon  becomes  prickling  and  tingling, 
and  extends  to  the  stomach  and  eventually  to  the  skin.  This  is  ac- 
companied by  a  profuse  flow  of  saliva,  and  often  by  vomiting.  The 
pulse  is  very  slow,  and  may  be  irregular,  and  later  becomes  weak  and 
imperceptible,  when  symptoms  of  collapse  appear.  The  respiration 
is  slow  and  labored,  and  great  muscular  weakness  is  complained  of. 
After  a  time  the  smarting  and  tingling  of  the  skin  are  no  longer  felt, 
and  on  examination  the  cutaneous  sensibility  is  found  to  be  much  re- 
duced. The  intelligence  remains  unimpaired  to  the  last  in  many  cases, 
although  unconsciousness  sometimes  occurs,  and  death  is  generally, 


AGONITINE.  329 

but  not  invariably,  preceded  by  convulsions.  The  pupil  is  unaffected 
except  when  convulsions  supervene,  when  it  is  dilated.  The  prickling 
of  the  throat  and  skin  is  the  most  characteristic  symptom,  and  is 
practically  diagnostic  in  cases  of  poisoning,  110  other  drug  excepting 
veratrine  having  this  effect.  Death  is  due  to  paralysis  of  the  respira- 
tory centre  from  the  direct  action  of  the  poison,  although  this  may  be 
aided  by  anaemia  of  the  medulla  from  the  imperfect  circulation. 

In  small  doses  aconitine  induces  slowing  of  the  heart  and  slight 
muscular  weakness,  which  is  often  accompanied  by  tingling  of  the 
lips,  tongue  and  throat. 

Action. — -The  prickling,  tingling  sensation  is  due  to  an  affection  of 
the  Terminal  Organs  of  the  Sensory  Nerves,  as  is  shown  by  its  appearing 
first  at  the  point  of  application  of  the  drug.  Thus,  when  aconitine  is 
swallowed  the  prickling  and  warmth  is  felt  in  the  lips,  tongue,  and 
throat,  and  after  small  doses  may  be  confined  to  these  parts,  while  if 
an  ointment  containing  aconitine  be  rubbed  on  the  skin,  the  same  sen- 
sation is  induced  locally.  But  no  redness  or  swelling  of  the  skin  is 
induced,  nor  are  blisters  formed,  so  that  aconitine  differs  entirely  from 
the  class  of  skin  irritants  (page  78).  It  evidently  acts  by  stimulat- 
ing the  terminations  of  the  sensory  nerves,  more  especially  those  of 
common  sensation,  while  the  other  sensory  end  organs  have  not  been 
shown  to  be  involved.  Thus,  apart  from  the  bitter  taste  which  it 
possesses  in  common  with  all  alkaloids,  aconitine  has  no  effect  upon  the 
taste  organs  during  this  stage.  The  stimulation  afterwards  passes  into 
depression,  which  induces  a  sense  of  numbness  at  the  point  of  applica- 
tion, and  in  cases  of  poisoning,  in  all  the  surfaces  of  the  body.  The 
taste  nerves  seem  to  be  involved  in  this  effect,  if  Laborde's  statement 
be  correct  that  sweet  substances  have  no  taste  after  aconitine.  The 
irritation  of  the  sensory  terminations  often  causes  a  number  of  reflexes, 
such  as  sneezing,  coughing,  increased  secretion  of  saliva  and  vomiting, 
although  some  of  these  may  be  due  in  part  to  stimulation  of  the 
medullary  centres.  Evidence  of  the  stimulation  of  Other  Terminations 
is  presented  in  fibrillary  twitching  of  the  muscles  in  the  frog  and 
sometimes  in  mammals.  This  is  prevented  by  curara,  but  not  by 
section  of  the  nerves,  and  is  therefore  attributed  to  stimulation  of  the 
terminations  of  the  motor  nerves  in  muscles.  The  muscles  themselves 
are  comparatively  little  affected.  Waller  states  that  even  minute 
quantities  of  aconitine  abolish  the  irritability  of  nerve  fibres  when  it 
is  directly  applied  to  them. 

The  effects  of  aconitine  on  the  Circulation  are  somewhat  complex,  as 
the  heart  is  affected  directly  by  it,  as  well  as  through  its  inhibitory 
nerves,  and  the  vaso-motor  centre  is  stimulated  in  addition.  The 
frog's  heart  is  first  accelerated  from  the  direct  action  of  the  poison,  but 
this  soon  passes  into  the  slow  pulse  and  prolonged  diastole  which  are 
characteristic  of  inhibitory  action.  The  subsequent  standstill  may  at 
first  be  removed  by  atropine,  but  somewhat  later  this  remedy  fails,  as 
the  drug  begins  to  act  directly  on  the  heart.  A  second  acceleration 
may  be  thus  induced,  but  the  contractions  soon  become  irregular,  and 


330  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

groups  of  almost  normal  beats  alternate  with  peristaltic  movements 
which  fail  to  expel  any  blood  from  the  heart.  Later,  the  larg^  contrac- 
tions may  alternate  with  periods  of  complete  quiescence  in  the  ventricle, 
while  the  auricles  continue  to  beat,  and  stimulation  of  the  accelerans 
nerve  is  followed  by  periods  of  regular  contraction.  The  heart  muscle 
seems  to  have  lost  in  great  part  its  power  of  conducting  impulses,  so 
that  the  contraction  of  the  auricle  often  fails  to  excite  a  ventricular 
systole ;  but  if  the  conductivity  be  increased  by  stimulation  of  the 
accelerator  nerve,  or  if  the  ventricle  be  excited  by  a  series  of  electric 
shocks,  it  responds  by  rhythmical  contractions. 

In  mammals,  the  preliminary  quickening  of  the  heart  is  masked  by 
the  strong  stimulation  of  the  vagus  centre.  This  produces  marked 
slowing  of  the  pulse,  an  increased  dilation  in  diastole  and  a  lessened 
systolic  contraction;  the  amount  of  blood  leaving  the  heart  is  consider- 
ably reduced  and  the  circulation  is  slackened.  These  symptoms  are  the 
only  ones  seen  in  the  heart  except  With  very  large  doses  of  the  drug. 
They  are  shown  to  be  due  to  the  action  on  the  inhibitory  centres  in 
the  medulla  by  the  fact  that  section  of  the  vagus  brings  the  heart  back 
to  its  normal  rate  and  extent  of  contraction.  In  medicinal  doses,  then,| 

4  the  only  effect  of  aconitine  on  the  heart  is  due  to  the  vagus  stimulation,! 

?  the  direct  cardiac  action  not  coming  into  play,  and  the  administration! 

I  of  aconite  in  therapeutics  is  one  of  the  best  methods  of  eliciting  pure^ 
and  unmixed  inhibition. 

In  fatal  doses,  aconitine  exerts  a  further  action  on  the  heart,  how- 
ever, for  the  direct  muscular  action  now  comes  into  play  and  the 
heart  suddenly  accelerates  from  the  slow  vagus  rhythm  to  one  far  above 
the  normal.  At  the  same  time  it  becomes  irregular,  with  a  tendency 
towards  the  formation  of  groups  of  imperfect  contractions  and  of  con- 
tractions originating  in  the  ventricles  independently  of  the  auricles.  As 
the  action  becomes  more  intense,  the  irregularity  increases,  and  eventu- 
ally the  heart  passes  into  delirium.  A  curious  fact  has  been  noted  by 
several  observers  —  that  after  section  or  paralysis  of  the  vagus,  a  much 
larger  quantity  of  aconitine  is  required  to  produce  the  acceleration  and 
final  delirium  than  when  the  nerves  are  intact.  It  has  generally  been 
stated  that  the  cause  of  the  acceleration  is  paralysis  of  the  vagus  termi- 
nations, but  besides  this  there  is  evidently  strong  stimulation  of  the 
cardiac  muscle,  for  the  acceleration  occurs  after  division  of  the  vagi 
and  even  in  the  excised  heart.  The  auriculo-ventricular  rhythm  is 
disturbed,  the  auricle  often  beating  at  a  different  rate  from  the  ven- 
tricle, and  the  alternate  consonance  and  dissonance  of  their  contractions 
partly  explains  the  variations  in  the  ventricular  rhythm  and  strength. 
The  blood-pressure  in  mammals  falls  rapidly  from  the  lessened  out- 
put of  the  heart  in  the  stage  of  vagus  stimulation.  There  is  some 
evidence  of  an  action  on  some  part  of  the  vaso-motor  mechanism  as 
well,  for  some  observers  have  noted  a  rise  in  arterial  pressure  after 
aconitine  in  animals  in  which  the  vagi  had  been  divided  or  paralyzed 
before  the  exhibition  of  the  drug.  The  fact  that  the  vagus  centre  is  so 
strongly  stimulated  would  also  suggest  the  probability  of  some  increase 


ACONITINE.  331 

in  the  activity  of  the  vase-motor  area.  After  the  stage  of  acceleration 
has  set  in,  the  blood-pressure  becomes  extremely  irregular,  alternately 
sinking  to  zero  and  remaining  at  tlfat  point  for  some  seconds  and  again 
attaining  a  fair  height.  These  variations  are  evidently  due  to  the 
alternations  in  the  heart's  movements.  The  vaso-motor  centre  seems 
eventually  to  become  paralyzed,  for  it  has  been  found  that  stimulation 
of  an  afferent  nerve  produced  no  change  in  the  tension,  while  stimula- 
tion of  the  efferent  vaso-motor  nerves  still  caused  a  marked  increase. 
The  vaso-motor  nerves  and  their  terminations  in  the  periphery  seem  to 
be  unaffected  by  this  poison. 

The  Respiration  is  early  affected  by  acouitine ;  it  becomes  much 
slower,  the  movements  are  more  labored  than  normally,  and  the  ani- 
mal suffers  from  marked  dyspnoea.  The  accessory  respiratory  muscles 
contract  vigorously,  and  the  movements  of  the  abdominal  expiratory 
muscles  are  so  powerful  as  to  suggest  the  movements  of  vomiting 
rather  than  of  respiration.  In  fatal  cases  the  respiration  soon  be- 
comes interrupted  by  convulsions,  and  in  the  intervals  between  these 
becomes  weaker  and  eventually  ceases.  Various  explanations  of  the 
respiratory  phenomena  have  been  given.  It  is  certainly  not  due  to 
action  on  the  phrenic  terminations,  for  the  diaphragm  contracts  on 
electrical  stimulation  of  these  nerves  after  its  spontaneous  movements 
have  ceased.  The  dyspnoea  resembles  somewhat  that  seen  on  stimu- 
lation of  the  centripetal  fibres  of  the  vagus,  and  the  theory  has  been 
propounded  that  aconitine  stimulates  the  vagus  terminations  in  the 
lungs  in  the  same  way  as  the  sensory  terminations  in  the  skin.  The 
same  dyspnoea  is  seen,  however,  when  aconite  is  given  after  section  of 
the  vagi,  so  that  it  seems  to  be  due  to  some  action  on  the  respiratory 
centre. 

The  action  of  aconitine  on  the  Central  Nervous  System  is  still  a 
matter  of  dispute,  as  the  effects  on  the  peripheral  nerve-ends  tend  to 
obscure  the  symptoms,  but  there  can  be  no  doubt  that  certain  parts  are 
stimulated.  Thus,  the  vagus  centre  is  undoubtedly  thrown  into  a  con- 
dition of  increased  irritability,  for  inhibition  of  the  heart  is  a  marked 
feature  of  the  action.  Probably  the  vaso-constrictor  centre  also  under- 
goes some  stimulation,  and  the  vomiting  so  often  seen  may  be  caused, 
at  least  in  part,  by  increased  irritability  of  the  medullary  centres. 
The  convulsions  seen  in  both  cold-  and  warm-blooded  animals  also 
point  to  central  stimulation,  and  the  respiratory  symptoms  are  certainly 
of  central  origin,  though  their  explanation  is  still  unknown.  The 
higher  centres  seem  to  be  almost  unaffected  by  the  drug,  for  conscious- 
ness has  often  remained  to  the  end,  and  when  this  is  not  the  case,  the 
mental  symptoms  are  to  be  ascribed  to  the  changes  in  the  heart  and 
respiration.  The  stimulation  produced  by  aconitine  is  therefore  con- 
fined to  some  of  the  lower  divisions  of  the  central  nervous  system  — 
more  particularly  to  the  medulla  oblongata.  Some  authors  suppose 
that  the  paralyzing  action  which  succeeds  the  stimulation,  is  more 
marked  in  the  sensory  than  in  the  motor  sphere  and  as  evidence  of  this 
it  has  been  pointed  out  that  in  frogs  the  reflexes  disappear  before  the 


332  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

voluntary  movements,  but  this  is  explained  by  the  anaesthetic  action  of 
aconitine  on  the  skin  and  cannot  be  accepted  as  evidence.  The  paralysis 
advances  much  more  rapidly  in  the  respiratory  centre  than  elsewhere 
and  death  occurs  from  asphyxia,  while  the  rest  of  the  central  nervous 
system  is  shown  to  be  still  irritable  by  the  occurrence  of  convulsions. 

The  muscular  weakness  often  complained  of  after  comparatively  small 
quantities  may  be  due  to  the  depression  of  the  circulation  through  the 
inhibitory  action,  or  to  nausea. 

The  Secretion  of  saliva  is  greatly  increased  by  aconitine  from  the 
irritation  of  the  sensory  terminations  in  the  mouth  and  from  the  nausea. 
The  cold  perspiration  observed  in  poisoning  may  be  ascribed  to  the 
collapse  rather  than  to  any  direct  action  on  the  sweat  glands,  although 
Aubert  states  that  aconitine  is  a  powerful  diaphoretic  in  itself. 

Acouitine  causes  a  marked  fall  of  Temperature  both  in  fever  and  in 
normal  animals,  but  the  precise  way  in  which  this  action  is  elicited  is 
unknown.  Brunton  and  Cash  found  that  after  aconite  the  temperature 
fell  more  rapidly  than  usual  if  the  animal  was  kept  in  a  cool  bath,  but 
rose  more  readily  if  it  was  subjected  to  external  warmth.  The  fall  in 
temperature  is  generally  ascribed  to  the  depression  of  the  circulation 
from  the  inhibitory  action,  but  this  observation  would  seem  to  indicate 
that  aconite  also  acts  upon  the  centres  regulating  the  temperature  of 
the  body. 

In  cases  of  Poisoning  in  animals  atropine  has  been  found  to  alleviate 
the  symptoms  and  not  infrequently  to  lead  to  recovery  after  doses  which 
would  otherwise  have  been  fatal.  This  improvement  is  more  espe- 
cially marked  in  the  respiration  which  may  resume  its  normal  charac- 
ter and  persist  until  heart  paralysis  sets  in.  Boehm  explained  this  by 
a  supposed  action  on  the  terminations  of  the  vagus  in  the  lung,  but  it 
is  more  probably  to  be  ascribed  to  the  stimulant  action  of  atropine  on 
the  respiratory  centre.  In  those  cases  the  cause  of  death  is  said  to  be 
cardiac  paralysis,  but  the  stage  of  irregularity  and  the  final  delirium 
cordis  is  certainly  retarded  very  considerably  by  atropine.  Atropine 
appears  to  be  the  antidote  from  which  most  is  to  be  hoped  for  in  cases 
of  aconite  poisoning. 

Aconitine  is  Excreted  mainly  by  the  urine.  Minute  quantities  have 
also  been  found  in  the  saliva  and  bile. 

Benzaconine  is  very  much  less  poisonous  than  aconitine  and,  in  fact,  can 
scarcely  be  included  among  active  poisons,  though  very  large  quantities  act 
on  the  heart,  slowing  it  and  rendering  it  irregular,  and  also  depress  the 
respiration .  It  has  no  effect  on  the  sensory  terminations.  Aconine  itself  is 
almost  inactive,  but  large  quantities  strengthen  the  heart  beat  and  paralyze 
the  terminations  of  the  motor  nerves  like  curara.  It  seems  unlikely  that 
these  alkaloids  have  any  influence  on  the  action  of  the  aconite  preparations, 
although  the  possibility  cannot  be  excluded  at  present. 

The  alkaloids  obtained  from  some  other  species  of  Aconitum  have  been 
found  to  differ  considerably  from  aconitine  and  pseudaconitine  in  their  ac- 
tion. In  Aconitum  septentrional e  three  bases  lappaconitine,  septentrionaline 
and  cynoctonine  have  been  discovered.  Lappaconitine  causes  clonic  convul- 
sions, vomiting,  dyspnoaa  and  finally  paralysis  of  the  respiration  and  heart, 


ACONITINE.  333 

aiid  in  the  frog  lessens  the  sensibility  of  the  skin.  Septentrionaline  does  not 
cause  poisoning  when  taken  internally,  but  injected  subcutaneously  induces 
local  anaesthesia  and  later  paralysis  of  the  motor  terminations  like  curara. 
Cynoctouine  is  also  inactive  when  swallowed  and  is  less  poisonous  than  the 
others  when  applied  by  hypodermic  injection  when  it  causes  tonic  and 
clonic  convulsions  which  are  not  generally  followed  by  paralysis.  Two 
alkaloids,  lycaconitine  and  myoctonine,  have  been  found  in  Aconitum  lycocto- 
num,  and  induce  almost  identical  symptoms.  They  increase  the  reflex 
excitability,  and  this  is  followed  by  convulsions  and  later  by  paralysis  of  the 
terminations  of  the  motor  nerves  and  by  failure  of  the  heart. 

PREPARATIONS. 

Aconitum  (U.  S.  P.),  Aconiti  Radix  (B.  P.),  the  root  of  Aconitum  Na- 
pellus,  monk's-hood. 

TINCTURA  ACONITI  (U.  S.  P.),  1-5  drops  every  1-3  hours. 

TINCTURA  ACONITI  (B.  P.),  5-15  mins.     If  frequently  repeated,  2-5  mins. 

Fluidextractum  Aconiti  (U.  S.  P.),  0.05-0.1  c.c.  (1-2  mins.). 

Linimentum  Aconiti  (B.  P.). 

Aconitina  (U.  S.  P.,  B.  P.),  an  alkaloid  obtained  from  aconite  root.  It  is 
almost  insoluble  in  water  but  is  freely  soluble  in  alcohol.  Commercial  aconitine 
very  often  contains  large  amounts  of  aconine  and  benzaconine,  and  therefore 
varies  considerably  in  activity. 

Unguentum  Aconitino3  (B.  P.),  2  per  cent. 

Staphisagria  (U.  S.  P.),  Staphisagriae  Semina  (B.  P.),  the  dried  ripe  seeds 
of  Delphinium  staphisagria,  stavesacre. 

Fluidextractum  Staphisagrice,  0.05  c.c.  (1  min.). 

Unguentum  Staphisagrice,  (B.  P.). 

Therapeutic  Uses.  —  Aconite  is  employed  to  a  considerable  extent  in 
England,  the  United  States  and  France,  while  it  has  fallen  into  disuse 
in  some  other  countries.  Its  pharmacological  action  suggests  its  use 
to  slow  and  weaken  the  heart  and  circulation,  to  lower  the  temperature 
and  to  benumb  the  terminations  of  the  sensory  nerves  in  the  skin. 
Digitalis  is  often  prescribed  to  slow  the  pulse,  but  it  has  other  effects 
on  the  heart  and  circulation,  and  where  these  are  not  indicated,  aconite 
may  well  be  used.  Both  drugs  slow  the  pulse  in  the  same  way,  but 
while  aconite  slackens  the  circulation  and  lowers  the  blood-pressure, 
digitalis  accelerates  the  blood  current  and  increases  the  arterial  tension. 

The  temperature  is  also  reduced  by  aconite,  but  the  newer  antipy- 
retics have  supplanted  it  for  this  purpose,  as  they  are  more  certain  and 
more  powerful  in  their  effects.  The  tincture  is  still  prescribed  how- 
ever, and  ought  to  be  given  in  small  repeated  doses.  When  fever 
is  attended  by  a  very  quick  pulse,  aconite  is  especially  likely  to  be  of 
service,  but  it  ought  to  be  avoided  when  the  heart  is  very  weak. 

The  action  of  aconitine  on  the  sensory  nerve  terminations  has  been 
taken  advantage  of  in  cases  of  neuralgia,  and  there  is  decidedly  much 
more  reason  for  its  use  than  for  that  of  the  great  majority  of  drugs 
reputed  to  be  beneficial  in  this  condition.  Either  the  tincture,  or  a  2 
per  cent,  solution  of  the  alkaloid  in  oil,  or  the  ointment  of  the  B.  P. 
may  be  employed  externally.  Aconitine  has  also  been  injected  sub- 
cutaneously (Y^-JO-  mg-)  'in  neuralgia,  but  this  mode  of  application 
is  not  to  be  recommended,  as  it  causes  very  severe  pain,  which  in  some 


334  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

cases  lasts  a  long  time.  The  internal  administration  of  aconite  in 
neuralgia  does  not  seem  to  be  followed  by  any  improvement.  Staves- 
acre  is  scarcely  used  in  medicine  at  present. 

BIBLIOGRAPHY. 

Liegeois  et  Hottot.     Journ.  dela  Physiol.,  1861,  iv.,  p.  520. 

Pluyye.     Virchow's  Arch.,  Ixxxvii.,  p.  410. 

Ringer  and  Murrell.     Journ.  of  Physiol.,  i.,  p.  232. 

Boehm  u.  Wartmann.     Verhandl.  d.  phys.-med.  Gesellsch.  zu  Wiirzburg,  1872,  p.  63. 

Eu-erx.     Arch.  f.  exp.  Path.  u.  Pharm.,  i.,  p.  385. 

Anrep.     Arch.  f.  [Anat.  u.]  Phys.,  1880.     Supplemen.,  p.  161. 

Lubbe.     Inaug.  Diss.,  Dorpat,  1890. 

Dohrmann.     Inaug.  Diss.,  Dorpat,  1888. 

Rosendahl.  Arb.  a.  d.  pharmak.  Instit.  Dorpat,  xi.,  p.  1  (very  complete  bibliography 
up  to  1895). 

Matthews.     Journ.  of  Exp.  Med.,  ii.,  p.  593. 

Cash  and  Dimstan.  Transactions  of  the  Royal  Society,  cxc.,  p.  239 ;  ccviii.,  p.  39, 
and  ccix.,  p.  97. 

Schiller.     Arch.  f.  Anat.  u.  Phys.,  1904,  p.  248.      (Delphinine. ) 

XVII.     VERATRINE. 

Several  species  of  the  genus  Veratrum  have  been  found  to  contain 
alkaloids,  the  most  important  of  which  resemble  each  other  in  many 
respects,  and  also  present  many  points  of  analogy  to  those  of  the 
preceding  group. 

The  chief  members  of  this  series  are  Veratrine  (cevadine)  and  Proto- 
veratrine,  the  former  of  which  is  found  in  Veratrum  Sabadilla  (Asagrsea 
officinalis  or  Schoenocaulon  officinale),  cevadilla,  and  in  Veratrum 
viride,  Green  Hellebore,1  while  the  latter  is  the  chief  active  principle 
of  Veratrum  album,  White  Hellebore.1 

Each  of  these  alkaloids  is  accompanied  by  a  number  of  others,  most  of 
which  are  entirely  inactive,  while  several  of  them  are  only  weak  poisons 
and  possess  little  interest.  In  cevadilla,  in  addition  to  Veratrine,  there  are 
found  Cevadilline,  Sabadine,  Sabadinine  and  another  base,  which  is  known 
as  the  Veratrine  of  Wright  or  Couerbe.  In  white  hellebore  Protoveratrine 
is  accompanied  by  Jervine,  Pseudojervine,  Rubijervine,  Protoveratridine  and 
others.  Green  hellebore  contains  a  little  Verairine  along  writh  Jervine,  Pseu- 
dojervine  and  Rubijervine.  Jervine,  Sabadine  and  Sabadinine  are  known  to 
possess  some  action  on  the  organism  ;  cevadilline  and  Wright's  veratrme  have 
not  been  examined,  while  the  others  are  said  to  be  inactive. 

Veratrine  (C32H49NO0)  and  protoveratine  (C?2H51NOn)  are  both 
powerful  alkaloids,  the  latter  almost  rivaling  aconitine  in  its  toxicity. 
Veratrine  can  be  decomposed  into  angelic  acid  and  a  base,  cevine, 
which  seems  to  be  nearly  related  to  aconine.  Protoveratine  is  prob- 
ably a  combination  of  isobutyric  acid  and  a  similar  base.  Veratrine 
occurs  in  two  forms,  one  crystalline,  the  other  amorphous  ;  the  one 
passes  easily  into  the  other,  and  their  effects  are  identical  in  animals. 

1  Hellebore  is  also  the  popular  name  of  Helleborus  niger,  which  differs  entirely  from 
Veratrum  in  its  principles  and  also  in  its  action. 


VEEATRINE.  335 

The  effects  of  veratrine  on  the  central  nervous  system  and  the  sen- 
sory terminations  resemble  those  of  aconitine  very  closely.  On  the 
other  hand  the  muscles  present  a  curious  reaction  to  veratrine,  which 
is  entirely  absent  in  aconitine  poisoning. 

Symptoms. — The  symptoms  in  man  and  other  mammals  commence 
with  prickling  and  burning  in  the  mouth  followed  by  a  sensa- 
tion of  warmth  in  the  stomach,  marked  salivation,  nausea,  and 
vomiting.  The  bowel  is  more  involved  in  the  effects,  than  is  the  case 
in  aconitine  poisoning,  for  violent  purging  accompanied  by  severe  colic 
is  a  common  symptom.  The  prickling  sensation  soon  spreads  from  the 
mouth  and  throat  to  the  skin,  and  is  generally  followed  by  profuse  per- 
spiration. The  pulse  becomes  slow  and  irregular,  the  respirations 
slow  and  labored.  Fibrillary  contractions  of  the  muscles  and  convul- 
sions are  generally  observed,  and  after  some  time  collapse  sets  in  and 
is  followed  by  unconsciousness  and  eventually  by  respiratory  failure. 

Action.  —  When  veratrine  is  applied  in  ointment  to  the  Skin  the  same 
prickling,  warm  sensation  may  be  elicited  locally,  and  some  of  the 
poison  is  absorbed,  as  is  shown  by  these  symptoms  sometimes  occur- 
ring in  other  parts  of  the  body.  The  cause  of  this  is,  as  in  the  case  of 
aconite,  stimulation  of  the  terminations  of  the  sensory  nerves.  This 
action  causes  violent  sneezing  and  coughing  when  small  quantities  of 
veratrine  come  in  contact  with  the  sensitive  mucous  membranes  of  the 
nose  and  throat  and  the  Sabadilla  is  therefore  known  popularly  in 
Germany  as  Nieswurz  (Sneeze-wort).  After  the  irritant  action  has 
lasted  for  some  time,  the  sensory  terminations  in  the  skin  become  less 
sensitive,  and  a  feeling  of  numbness  and  of  cold  is  noted.  Protovera- 
trine  seems  to  cause  less  irritation  of  the  sensory  terminations  than 
veratrine,  and  the  subsequent  local  anaesthesia  is  more  complete. 

The  Terminations  of  the  Motor  Nerves  are  paralyzed  in  the  frog  by 
large  quantities  of  veratrine,  but  this  paralysis  is  not  preceded  by  an 
increase  in  their  irritability,  as  was  formerly  supposed. 

The  Nausea  and  Vomiting  which  are  invariably  present  in  veratrine 
poisoning,  may  be  due  in  part  to  the  irritation  of  the  sensory  termina- 
tions of  the  stomach,  but  must  probably  be  attributed  for  the  chief 
part  to  central  action.  The  salivation  may  be  merely  secondary  to 
this  emetic  effect,  or  the  poison  may  act  on  the  salivary  gland  di- 
rectly. Nothing  is  known  with  certainty  regarding  the  cause  of  the 
Purgation,  but  it  is  presumably  induced  by  some  action  on  the  nervous 
mechanism  of  the  intestine.  The  profuse  Perspiration  which  follows 
the  injection  of  large  quantities  of  veratrine,  and  the  cutaneous  secre- 
tion noted  in  the  frog,  have  been  attributed  to  stimulation  of  the  ter- 
minations of  the  nerves  regulating  the  activity  of  the  glands. 

The  most  characteristic  action  of  veratrine,  however,  is  that  on  the 
Striated  Muscles.  If  a  small  quantity  be  injected  into  the  lymph-sac 
of  a  frog  a  curious  clumsiness  and  awkwardness  in  the  movements 
becomes  apparent,  and  after  a  few  minutes  it  is  evident  that  this  is 
due  to  inability  to  relax  its  muscles.  When  a  muscle  is  exposed,  it  is 
seen  to  contract  as  rapidly  as  usual,  but  instead  of  immediately  relax- 


336 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


ing  again,  it  remains  shortened  and  offers  resistance  to  the  contraction 
of  the  opposing  muscles.  The  animal  can  no  longer  coordinate  its 
movements  therefore ;  for  example,  it  can  no  longer  extend  a  limb 


FIG.  32. 


sive  contractions  taken  at  intervals  of  one  minute,  five  minutes  after  the  injection  of  veratrine.  The 
contraction  is  higher  and  much  more  prolonged  than  in  a,  and  the  lever  returns  very  slowly  to  the 
base  line. 

immediately  after  flexing  it,  as  it  does  ordinarily  in  crawling,  and  loco- 
motion becomes  very  slow  and  ungainly. 

This  characteristic  action  is  most  easily  seen  on  comparing  the 
tracings  obtained  from  a  muscle  stimulated  directly  by  single  induction 
shocks  before  and  after  the  application  of  veratrine  (Fig.  32).  In  the 
first  part  of  the  tracing  it  will  be  observed  that  the  height  of  the  con- 
traction is  increased  by  veratrine,  but  this  feature  sinks  into  the  back- 
ground before  the  marked  prolongation  of  the  second  part  of  the  curve. 
Instead  of  the  almost  instantaneous  return  to  the  base  line  seen  in  the 
normal  tracing,  the  curve  shows  generally  a  slight  undulation,  and  then 
a  very  slow  fall,  the  period  of  relaxation  generally  being  20-30  times 
as  long  as  that  in  the  unpoisoned  muscle,  and  the  whole  contraction 
lasting  5-10  seconds  in  favorable  circumstances.  If,  however,  the 
muscle  be  stimulated  repeatedly  at  short  intervals,  so  as  to  induce 
fatigue,  the  length  of  the  curve  decreases  until  it  cannot  be  distin- 
guished from  the  ordinary  muscle  tracing ;  a  similar  effect  is  produced 
by  subjecting  it  to  cold,  or  by  heating  it  beyond  a  certain  point,  while 
moderate  heat  increases  the  abnormalities  of  the  tracing.  If  an  un- 
poisoned muscle  be  stimulated  repeatedly,  so  as  to  induce  fatigue,  and 
veratrine  be  then  injected,  it  is  found  that  a  marked  improvement  in 
the  contraction  occurs,  so  that  while  fatigue  lessens  the  prolongation 
of  the  veratrine  curve,  veratrine  removes  to  some  extent  the  effect  of 
fatigue.  In  the  prolonged  contraction  more  energy  is  used  up  than 
usual,  and  the  amount  of  heat  formed  during  muscular  contraction  is 
therefore  increased  by  veratrine.  Besides  the  alterations  seen  in  the 
tracing,  veratrine  increases  the  irritability  and  absolute  strength,  so 


VERATRINE.  337 

that  the  muscle  reacts  to  weaker  stimuli  and  contracts  against  a  greater 
weight  than  usual. 

The  muscular  phenomena  are  best  observed  in  the  frog,  but  can  also 
be  elicited  in  warm-blooded  animals,  although  in  the  latter  they  do  not 
play  such  an  important  role  in  the  symptoms  of  poisoning.  In  the 
frog,  the  muscle  is  finally  paralyzed,  but  this  does  not  occur  in  mam- 
mals, as  here  the  respiratory  centre  fails  long  before  the  quantity  of 
veratrine  necessary  to  induce  this  effect  has  been  absorbed. 

The  first  explanation  that  suggests  itself  for  the  curious  muscular 
phenomena,  that  they  are  due  to  some  change  in  the  nervous  system, 
is  negatived  by  the  fact  that  excised  muscles  show  exactly  the  same 
reaction.  Bezold  explained  the  prolongation  by  supposing  that  a 
change  was  produced  in  the  muscle  substance,  by  virtue  of  which  a 
single  stimulus  was  enabled  to  set  up  a  tetanic  contraction  ;  but  this  is 
shown  to  be  incorrect,  for  if  the  nerve  of  another  nerve-muscle  prepa- 
ration be  laid  on  the  veratrinized  muscle,  no  secondary  tetanus  is  set  up 
in  it,  as  would  be  the  case  if  the  first  muscle  were  undergoing  tetanic 
contraction.  The  generally  accepted  view  is  that  veratrine  increases 
the  catabolic  changes  in  muscle,  and  thereby  induces  a  prolongation  of 
the  period  of  active  contraction,  as  well  as  an  increase  in  the  height  of 
contraction  and  in  the  absolute  strength.  Fatigue,  by  reducing  the 
amount  of  substance  capable  of  undergoing  catabolic  change,  and  cold, 
by  increasing  its  stability,  counteract  the  effects  of  veratrine. 

In  the  tracing  of  veratrinized  muscle  a  curious  undulation  is  frequently 
seen  at  the  top  of  the  contraction,  or  the  ascent  may  at  first  be  rapid,  then 
slower,  and  then  again  more  rapid.  This  has  been  ascribed  to  veratrine 
acting  differently  on  the  two  forms  of  muscle  fibre,  the  gray  and  the  red,  but 
this  explanation  has  recently  been  shown  to  be  erroneous  (Carvallo  and 
Weiss).  Botazzi  supposes  that  the  initial  contraction  is  due  to  the  aniso- 
tropous  substance,  while  the  secondary  slower  and  prolonged  contraction  is 
induced  by  increased  activity  of  the  sarcoplasm.  The  electrical  organ  of 
the  torpedo  is  apparently  affected  by  veratrine  in  the  same  way  as  striated 
muscle. 

Waller  has  recently  shown  that  veratrine  abolishes  the  irritability 
of  the  peripheral  nerves  when  a  solution  is  applied  to  them  directly. 

Protoveratrine  differs  entirely  from  veratrine  in  its  effects  on  the 
muscles  and  the  terminations  of  the  motor  nerves.  The  latter  are  not 
paralyzed  even  by  the  largest  quantities,  while  the  contraction  of  the 
muscle  is  rather  shortened  than  prolonged.  The  contraction  is  higher 
and  the  absolute  strength  is  increased,  but  fatigue  is  induced  more 
readily  than  in  the  unpoisoned  muscle,  so  that  protoveratrine  appears 
"to  increase  the  muscular  force  temporarily,  but  leads  to  its  early  ex- 
haustion. 

Circulation.  —  The  ventricular  muscle  of  the  frog's  heart  is  affected 
by  veratrine  in  very  much  the  same  way  as  the  ordinary  striated 
muscle,  while  the  auricular  muscle,  consisting  chiefly  of  unstriated 
fibres,  is  much  less  altered.  The  ventricular  systole  is  at  first  stronger 
and  more  prolonged ;  somewhat  later  one  part  of  the  ventricle  is  seen 
22 


338  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

to  remain  contracted  during  the  alternate  diastoles  of  the  rest,  and 
waves  of  contraction  spread  over  the  heart  resembling  the  peristaltic 
movements  of  the  intestine  rather  than  the  ordinary  contractions  of 
the  heart.  The  whole  ventricle  is  smaller  than  usual,  and  but  little 
blood  is  expelled  into  the  aorta.  Still  later  the  persistent  contraction 
spreads  over  the  whole  ventricle,  so  that  it  dilates  only  half  as  often 
as  it  did  at  first,  while  the  auricles  maintain  their  original  rhythm. 
This  is  evidently  due  to  action  on  the  muscle ;  the  contraction  is  so 
prolonged  as  to  limit  the  number  of  diastoles,  and  the  ventricle  can 
therefore  react  only  to  every  alternate  contraction  of  the  auricle. 
After  this  "  half-rhythm  "  has  persisted  for  some  time,  the  contractions 
become  slower  and  weaker,  and  the  heart  finally  comes  to  a  standstill. 
The  behavior  of  a  frog's  heart  under  veratrine  resembles  closely  that 
characteristic  of  the  digitalis  series. 

In  mammals,  the  chief  circulatory  symptoms  arise  from  stimulation 
of  the  medullary  centres  resembling  that  seen  in  the  earlier  stages  of 
aconite  poisoning.  The  stimulation  of  the  cardiac  inhibitory  centre 
produces  slowing  of  the  heart  and  a  decrease  in  its  output,  while  at  the 
same  time  the  peripheral  vessels  are  contracted  by  the  increased  activity 
of  the  vaso-motor  centre.  After  larger  quantities  the  terminations  of 
the  vagus  are  paralyzed,  and  the  vaso-motor  centre  is  at  the  same  time 
depressed,  so  that  the  pulse  becomes  quicker,  but  the  blood-pressure  is 
somewhat  lowered.  In  the  mammalian  heart  no  such  prolongation  in 
the  systole  is  seen  as  in  the  frog's,  but  that  a  slight  stimulant  action 
is  exercised  by  veratrine  is  shown  by  the  fact  that  very  large  doses 
quicken  the  rhythm  even  after  atropine.  Veratrine,  therefore,  seems 
to  resemble  aconitine  in  its  effects  on  the  mammalian  circulation,  but 
much  larger  quantities  are  required  to  produce  the  same  effects,  and 
the  more  evident  symptoms  of  stimulation  of  the  myocardium  are  not 
elicited. 

The  Eespiratory  Changes  under  veratrine  also  resemble  those  under 
aconitine,  and  in  both  the  cause  of  death  is  the  same — paralysis  of  the 
respiration. 

The  Central  Nervous  System  seems  to  undergo  stimulation  under 
veratrine  as  under  aconitine.  This  is  evidenced  by  the  convulsions 
seen  in  mammals  as  well  as  by  the  stimulation  of  the  medullary  centres 
already  noted.  After  large  quantities  of  the  poison  this  stimulation 
gives  place  to  paralysis,  terminating  in  failure  of  the  respiration.  The 
highest  centres  seem  less  affected  than  the  spinal  cord  and  medulla 
oblongata,  for  complete  consciousness  has  remained  until  immediately 
before  death  in  several  fatal  cases. 

The  Temperature  is  sometimes  found  lower  than  the  normal  after 
veratrine,  probably  owing  to  the  slowing  of  the  circulation.  In  other 
cases,  when  the  convulsive  movements  are  very  marked  and  the  heat 
production  is  therefore  much  increased,  the  temperature  has  been 
found  somewhat  higher  than  usual.  In  cases  of  poisoning  in  mammals 
atropine  is  said  by  Lissauer  to  have  some  value,  probably  owing  to  its 
action  on  the  respiratory  centre  and  on  the  vagus  terminations  in  the  heart. 


EMETINE.  339 

As  regards  the  other  alkaloids  of  this  series,  jervine,  sabadilline  and  saba- 
dinine  seem  to  possess  the  same  action  as  veratrine,  but  are  much  less  poison- 
ous. Protoveratrine,  which  as  has  been  said,  differs  from  veratrine  chiefly 
in  not  prolonging  the  muscular  contraction  and  in  the  effects  on  the  sensory 
terminations,  is  much  more  poisonous.  Its  action  resembles  that  of  aconitine 
as  much  as  that  of  veratrine,  and  it  may  therefore  be  regarded  as  a  link  con- 
necting the  two  groups. 

PEEPARATIONS. 

Veratrina  (U.  S.  P.,  B.  P.),  a  mixture  of  alkaloids  obtained  from  the  seeds 
of  Asagrsea  officinalis  (U.  S.  P.);  a  mixture  of  alkaloids  prepared  from  ceva- 
dilla,  the  dried,  ripe  seeds  of  Schcenocaulon  officinale  (B.  P.),  forms  a  white 
or  gray,  amorphous  or  semi-crystalline  powder  without  odor,  but  causing  in- 
tense irritation  of  the  nostrils,  with  an  acrid  taste  and  leaving  a  sensation  of 
tingling  and  numbness  on  the  tongue.  It  is  insoluble  in  water  but  soluble 
in  alcohol.  It  contains  veratrine  and  the  other  alkaloids  of  the  plant. 

Unguentum  Veratrinx  (U.  S.  P.,  B.  P.). 

Oleatum  Veratrinse  (U.  S.  P.). 

Veratrum  (U.  S.  P.),  American  or  Green  Hellebore,  the  rhizome  and  roots 
of  Veratrum  viride. 

Fluidextractum  Veratri,  0.2-0.5  c.c.  (3—6  mins.). 

Tinctura  Veratri,  0.2-0.5  c.c.  (3-6  mins.). 

Therapeutic  Uses.  —  The  therapeutic  uses  of  the  members  of  this 
series  are  extremely  limited.  Veratrine  is  used  in  the  form  of  the 
oleate  or  ointment  as  an  external  application  in  cases  of  neuralgia,  and 
is  certainly  a  safer  remedy  than  aconite.  Neither  its  pharmacological 
action  nor  therapeutic  experience  supplies  any  indications  for  its  inter- 
nal use.  Yeratrum  viride  is  used  internally  in  the  same  class  of  cases 
as  aconite,  but  as  its  activity  is  due  to  veratrine  it  might  well  be  dis- 
carded from  the  pharmacopeia.  Yeratrum  album  is  also  a  superfluous 
drug. 

BIBLIOGRAPHY. 

Bezold  u.  Hirt.     Untersuch.  aus  dem  phys.  Laborat.  zu  Wiirzburg,  i.,  p.  75. 

Kolliker.     Virchow's  Archiv,  x.,  p.  257. 

Rossbach.     Ptiiiger's  Archiv,  xiii.,  p.  607. 

Lissauer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiii.,  p.  36. 

Brunton  and  Cash.    Journ.  of  Physiol.,  iv.,  p.  1. 

Overend.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi.,  p.  1. 

Eden.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix.,  p.  440.     (Protoveratrine.) 

Schenk.     Pfl tiger's  Archiv,.  Ixi.,  p.  494. 

Santesson.     Skand.  Arch.  f.  Phys.,  xiv.,  pp.  1,  430. 

Carvallo  etWeiss.     Joum.  de  Phys.  et  Pathol.,  i.,  p.  1. 

Garten.     Pfliiger's  Arch.,  Ixxvii.,  p.  485. 

Botazzi.     Areh.  f.  [Anat.  u.]  Phys.,  1901,  p.  377. 

Buchanan.     Journ.  of  Physiol.,  xxv.,  p.  137. 

XVIII.     EMETINE  (IPECACUANHA). 

Ipecacuanha  (Cephselis  Ipecacuanha)  has  long  been  used  for  its  emetic 
and  expectorant  virtues,  and  was  until  recently  believed  to  contain 
only  one  alkaloid,  Emetine.  Paul  and  Cownley  have  shown,  how- 
ever, that  this  so-called  principle  is  really  made  up  of  three  distinct 
alkaloids,  Cephceline  (C14H19NO2),  Emetine  (C14H18(CHS)NO2),  and 
Psychotrirw,  the  first  two  of  which  are  quinoline  derivatives  and  pro- 


340  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

duce  almost  identical  effects,  while  psychotrine  is  nearly  inert.  It 
seems  probable  that  one  or  both  of  them  are  formed  by  a  number  of 
other  plants,  some  of  which  have  been  used  as  emetics  in  former  times, 
and  among  which  may  be  mentioned  several  species  of  violet.  Their 
chief  action  is  exerted  on  the  alimentary  canal,  although  they  are  also 
local  irritants. 

Symptoms  and  Action.  —  When  administered  internally  emetine  has 
a  bitter,  acrid^jtaate,  and  produces  a  copious,  salivary,  secretion,  fol- 
lowed later  by  nausea  and  vomiting  with  the  usual  attendant  symp- 
toms. The  drug  is  generally  largely  eliminated  by  vomiting,  so  that 
no  further  effects  are  observed.  When  injected  hypodermically, 
however,  it  induces  nausea,  vomiting  and  purging,  and  blood  is  fre- 
quently voided  in  the  stools,  a  condition  of  collapse  follows,  and  the 
animal  generally  dies  of  exhaustion  in  the  course  of  a  few  hours  after 
the  onset  of  the  symptoms.  Very  large  quantities  injected  subcuta- 
neously  or  intravenously  may  fail  to  elicit  vomiting,  but  the  collapse 
symptoms  appear,  and  after  some  weak  convulsive  movements,  the 
animal  dies  of  cardiac  failure.  In  those  cases  in  which  death  follows 
rapidly  on  the  injection,  no  pathological  lesions  may  be  found  after 
death,  but  in  experiments  where  smaller  quantities  are  injected,  and 
the  animal  survives  for  18-24  hours,  the  stomach  and  intestine  often  ex- 
hibit the  appearances  of  an  acute  gastro-enteritis.  The  mucous  mem- 
brane is  swollen,  congested  and  often  covered  with  a  muco-purulent 
secretion  or  studded  with  ecchymoses,  and  in  dogs  ulceration  is  often 
present.  A  lesion  which  is  not  by  any  means  constant,  but  which 
occurs  in  a  considerable  number  of  animals  and  especially  in  rabbits, 
is  oedema  of  the  lungs. 

Emetine  possesses  a  gowerfuL  Irritant  Local  Action,  which  is,  how- 
ever, much  more  markeOmcertain  individuals  than  in  others.  The 
smallest  quantity  of  the  powdered  root  of  ipecacuanha  is  sufficient 
to  induce  in  the  subjects  of  this  idiosyncrasy  considerable  swelling 
and  injection  of  the  conjunctival  and  nasal  mucous  membranes,  with 
salivation,  tears,  sneezing,  coughing  and  bronchial  catarrh.  When 
applied  to  the  skin  as  a  liniment,  it  produces  redness,  itching  and  oc- 
casionally a  pustular  eruption,  but  Lowin  states  that  the  alkaloids  are 
devoid  of  action  on  the  subcutaneous  tissues.  Its  action  on  the 
alimentary  canal  also  indicates  its  irritant  properties.  It  has  been 
much  discussed  whether  the  emesis  is  wholly  due  to  this  irritant  action 
on  the  gastric  mucous  membrane,  or  whether  emetine,  like  apomor- 
phine,  has  a  specific  action  on  the  centres  in  the  medulla  oblongata  con- 
trolling vomiting.  In  view  of  the  fact  that  emetine,  like  many  other 
irritants  when  injected  subcutaneously,  has  a  specific  action  on  the  ali- 
mentary canal  it  seems  unnecessary  to  have  recourse  to  any  action  on 
the  central  nervous  system,  and  almost  all  the  facts  brought  forward 
as  evidence  of  this  supposed  central  action  have  been  disproved. 

It  is  sometimes  stated  that  section  of  the  vagus  nerves  does  not  prevent 
ipecacuanha  from  causing  vomiting,  whereas  if  it  only  irritated  the  stomach, 
the  division  of  these  nerves  (which  are  probably  the  chief  sensory  nerves  of 


EMETINE.  341 

the  stomach)  ought  to  prevent  it  by  hindering  the  impulses  reaching  the 
medulla  and  setting  up  reflex  processes  there.  But  this  statement  has  been 
contradicted,  and  no  great  weight  can  be  laid  on  the  argument  in  any  case, 
because  section  of  the  vagus  alone  causes  violent  and  persistent  vomiting  very 
often.  Thumas  states  that  the  application  of  emetine  solutions  to  the 
medulla  provokes  vomiting,  but  this  method  is  so  open  to  objection  that  his 
inference  that  the  alkaloid  acts  on  the  vomiting  centre,  can  hardly  be  re- 
garded as  justifiable.  On  the  other  hand,  it  may  be  urged  that  if  emetine 
acted  on  the  medullary  centre,  vomiting  ought  to  follow  after  smaller  doses 
and  more  quickly  when  it  is  injected  subcutaneously,  being  thus  more  rapidly 
absorbed,  than  when  it  is  taken  up  from  the  stomach.  But  this  is  not  the 
case,  for  ipecacuanha  causes  emesis  as  soon  and  in  as  small  quantities  when 
it  is  administered  by  the  stomach,  whereas  apomorphine  which  acts  on  the 
centre  directly,  acts  much  more  rapidly  and  efficiently  when  it  is  injected 
subcutaneously.  While  the  question  cannot  be  said  to  be  definitely  settled, 
almost  all  the  facts  point  to  peripheral  gastric,  and  not  to  central  action. 

Emetine  injected  into  a  vein  weakens  the  heart's  action,  and  induces  a  fall 
of  blood-pressure,  but  when  it  is  injected  subcutaneously  or  given  by  the 
mouth  the  heart  is  much  less  affected. 

In  the  frog,  emetine  does  not  cause  vomiting,  but  a  slowly  advancing  central 
paralysis  follows  its  injection,  the  spontaneous  movements  ceasing  early, 
and  later  the  reflex  excitability  disappearing.  The  contractions  of  the  heart 
are  rendered  weak  and  irregular,  and  eventually  cease  from  paralysis  of  the 
cardiac  muscle. 

The  striated  muscle  of  the  frog  has  been  said  to  be  weakened  and 
paralyzed  by  emetine,  but  this  has  been  disputed,  and  the  muscular  action 
is  in  any  case  slight  and  unimportant  in  frogs  poisoned  with  the  alkaloid. 

The  nausea  and  vomiting  are  accompanied  by  the  usual  symptoms  — 
muscular  weakness  and  depression,  increased  secretion  of  saliva  and  of 
mucus  by  the  glands  of  the  throat  and  respiratory  passages,  often  per- 
spiration and  generally  temporary  acceleration  of  the  pulse.  (See 
apomorphine,  p.  235.)  Most  of  the  researches  on  which  the  above 
statements  are  based  have  been  performed  with  a  mixture  of  the  alka- 
loids, but  the  two  chief  of  these  resemble  each  other  very  closely  in 
their  effects,  cephaBline  being  somewhat  more  powerful  than  pure 
emetine. 

Emetine  and  cephseline  have  not  been  used  in  practical  therapeutics, 
various  preparations  of  the  crude  drug  being  prescribed  instead.  Their 
isolation  is  so  difficult  that  it  seems  unlikely  that  the  pure  alkaloids 
will  be  made  use  of  in  the  near  future,  and  from  a  comparison  of  their 
effects  with  that  of  ipecacuanha  it  scarcely  seems  desirable  that  they 
should  be  introduced.  For  ipecacuanha  is  much  less  liable  to  produce 
purging  than  emetine,  probably  because  the  solution  of  the  alkaloids 
is  retarded  by  the  presence  of  large  quantities  of  tannin  bodies  and 
other  impurities,  while  at  the  same  time  the  emetic  action  is  but  little 
slower  than  that  of  emetine. 

PREPARATIONS. 

U.  S.  P. — Ipecacuanha,  the  root  of  Cephselis  Ipecacuanha.  The  powdered 
root  is  prescribed  in  dysentery  in  quantities  of  2-4  G.  (30-60  grs.);  emetic, 
2  G.  (30  grs.);  expectorant,  0.06-0.3  G.  (1-5  grs.). 


342  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Fluidextractum  Ipecacuanhas,  expectorant,  0.2-0,5  c.c.  (3—8  mins.);  emetic, 
2  c.c.  (30  mins.). 

SYRUPUS  IPECACUANHA,   \  expectorant,    0.1-1   c.c.    (2-15   mins.);   emetic, 

VINUM  IPECACUANHA,      )       2-4  c.c.  (£-1  fl.  dr.);  for  a  child. 

TINCTURA  IPECACUANHA:  ET  OPII  contains  10  per  cent,  opium,  i.  e.,  is  of 
the  same  strength  as  laudanum,  0.3-1  c.c.  (5-15  mins.). 

PULVIS  IPECACUANHAS  ET  OPII  (10  per  cent,  opium),  Dover's  Powder, 
0.3-1  G.  (5-15  grs.). 

B.  P.  —  Ipecacuanhas  Eadix,  the  dried  root  of  Psychotria  Ipecacuanha, 
expectorant,  J-  2  grs.;  emetic,  15-30  grs. 

Extractum  Ipecacuanha  Liquidum,  expectorant,  £-2  mins.;  emetic,  15-20 
mins. 

Acetum  Ipecacuanha?,  10-30  mins. 

VINUM  IPECACUANHA,  expectorant,  10-30  mins.  ;  emetic,  4-6  fl.  drs. 

Trochiscus  Ipecacuanha,  contains  J  gr.  of  the  powdered  root. 

TROCHISCUS  MORPHIN^E  ET  IPECACUANHA,  each  contains  ^  gr.  of  mor- 
phine hydrochloride. 

PULVIS  IPECACUANHA  COMPOSITUS,  Dover's  Powder,  10  per  cent,  opium, 
5-15  grs. 

Pilula  Ipecacuanha  cum  Scilla,  4-8  grs.  This  pill  is  formed  from  Dover's 
Powder,  and  contains  about  5  per  cent,  of  opium. 

Therapeutic  Uses.  —  Ipecacuanha  has  been  largely  employed  as  an 
emetic,  and  although  it  has  been  replaced  for  some  purposes,  notably 
in  cases  of  poisoning,  by  apomorphine,  it  still  has  a  certain  field  of  use- 
fulness in  cases  in  which  an  emetic  is  indicated  but  in  which  the  hypo- 
dermic method  is  objectionable,  as  in  children.  At  present,  ipecacuanha 
is  used  chiefly  as  an  expectorant  in  the  treatment  of  inflammatory 
conditions  of  the  respiratory  passages^  For  this  purpose  it  is  prescribed 
in  very  much  less  quantities  than~those  necessary  to  produce  emesis. 
It  acts  indirectly  through  its  nauseating  properties,  and  has  the  ad- 
vantage  that  its  action  is  much  more  prolonged  than  that  of  apomor- 
phine, and  at  the  same  time  is  not  so  depressant  as  that  of  several 
metallic  substances,  such  as  tartar  emetic,  which  are  used  for  the 
same  purpose.  It  increases  the  secretion  of  the  bronchial  mucous  mem- 
brane, and  further  tends  to  render  it  more  fluid,  so  that  the  mucus  can  be 
coughed  up  more  easily.  The  increased  secretion  may  also  be  of 
service  by  protecting  the  inflamed  and  irritable  membrane  from  the  cold 
air  and  thereby  lessening  the  cough,  and  in  order  to  strengthen  this  ac- 
tion ipecacuanha  may  be  prescribed  in  combination  with  opium,  either 
as  a  lozenge  or  in  the  famous  Dover's  powder.  When  the  secretion  of 
the  bronchi  is  already  excessive,  and  the  cough  is  rather  to  be  encour- 
aged than  repressed,  these  preparations  are  of  course  contraindicated. 

Ipecacuanha  is  also  employed  as  a  diaphoretic,  either  alone  or  more 
commonly  as  Dover's  powder.  The  perspiration  is  not  so  copious  as 
that  following  pilocarpine  and  other  diaphoretics,  but  resembles  rather 
that  produced  by  warmth  applied  to  the  skin.  Dover's  powder  is 
therefore  a  common  remedy  in  chills  and  in  commencing  catarrh  of  the 


resp 

Ipecacuanha  is  used  very  largely  in  dy^niery^  particularly  in  tropi- 
cal dysentery,  in  which  it  seems  to  act  almost  as  a  specific.     Its  effect 


COLCHICINE.  343 

is  attributed  by  some  authorities  to  the  large  amount  of  tannin,  con- 
tained in  the  root,  and  a  preparation  of  ipecacuanha  from  which  the 
alkaloids  have  been  removed  (Ipecacuanha  Deemetinisata)  is  said  to  be 
as  valuable  in  these  cases  as  the  unaltered  drug.  Others  are  inclined 
to  ascribe  some  of  the  virtues  of  ipecacuanha  to  the  alkaloids,  and  deny 
that  the  same  results  are  obtained  by  the  use  of  this  preparation.  The 
purified  powder  has  the  advantage  of  not  causing  any  nausea  or  vomit- 
ing, and  is  certainly  to  be  preferred  to  the  crude  root  if  the  claims  of 
its  advocates  prove  to  be  well  founded.  Very  large  quantities  of  the 
powdered  root  are  generally  required  in  dysentery.  Many  prescribe 
enough  to  cause  vomiting  at  first,  and  then  follow  this  up  with  smaller 
quantities  which  are  used  along  with  morphine  or  ice,  or  with  sina- 
pisms to  lessen  the  nausea  and  vomiting.  Others  give  a  few  drops 
of  laudanum  at  once,  and  when  the  medullary  irritability  is  thus 
reduced,  and  there  is  less  danger  of  vomiting,  prescribe  30-60  grs. 
(2-4  G.)  of  the  powdered  root,  and  continue  the  treatment  with 
smaller  doses. 

Ipecacuanha  has  been  recommended  in  very  small  quantities  as 
a  stomachic,  even  in  cases  of  vomiting,  and  its  action  on  the  mu- 
cous membrane  might  be  expected  to  be  of  value  in  some  cases  ;  but 
it  very  often  fails  to  have  any  eifect,  and  is  not  widely  used  for  this 
purpose. 

BIBLIOGRAPHY. 

Dyce  Duckworth.     St.  Bartholomew  Hospital  Keports,  v.,  p.  218  ;  vii.,  p.  91. 
Podwyssotzki.     Arch.  f.  exp.  Path.  u.  Pharm.,  xi.,  p.  231. 

Lowin,  Kimura,  and  Zepf.  Arch,  internat.  de  Pharmacodyn.,  xi.,  pp.  9,  405;  xii., 
p.  345. 

Wild.     Lancet,  1895,  ii.,  p.  1274. 


XIX.     COLCHICINE. 

Colchicine  and  colchicdne  are  two  nearly  related  bodies  found  in  the 
seeds  and  corrn  of  Colchicum  autumnale,  which  owes  its  activity  to 
their  presence.  They  are  generally  included  among  the  alkaloids,  but 
differ  from  the  other  members  of  this  class  in  possessing  an  acid  reac- 
tion. Their  chemical  structure  is  still  imperfectly  known,  but  they 
do  not  seem  to  contain  a  pyridine  ring ;  colchicine  [CrH9(OCH3)3- 
(NHCOCH3)COOCH3]  is  the  methyl  ether  of  colchiceine  [C15H9- 
(OCH3)3(NHCOCH3)COOH] .  These  two  principles  are  apparently 
identical  in  their  effects,  which  are  observed  chiefly  in  the  alimentary 
canal. 

Symptoms.  —  No  symptoms  whatever  follow  the  use  of  colchicum  in 
ordinary  therapeutic  quantities.  After  the  administration  of  a  poison- 
ous dose  to  man  or  animals  several  hours  elapse  before  any  symptoms 
are  elicited,  and  the  amount  injected  has  but  little  influence  on  the 
duration  of  this  preliminary  stage.  Whether  given  by  mouth  or  hypo- 
dermically,  colchicine  produces  symptoms  of  discomfort  in  the  stomach 


344  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

and  intestine.  Pain  in  the  gastric  region  is  followed  by  salivation, 
nausea,  vomiting,  and  diarrhoea.  At  first  the  evacuations  are  the 
ordinary  contents  of  the  stomach  and  intestine,  but  afterwards  a  quan- 
tity of  sticky  mucous  fluid  may  be  ejected,  often  streaked  with  blood. 
Later,  a  condition  of  depression,  apathy  and  collapse  follows,  and  the 
movements  become  slow  and  difficult,  more  especially  in  the  posterior 
extremities,  which  eventually  become  completely  motionless ;  the 
paralysis  then  progresses  upwards*  until  the  movements  of  the  fore 
limbs  and  respiratory  muscles  are  involved,  when  death  occurs  from 
asphyxia.  In  man,  the  intelligence  remains  until  death,  though  there 
is  generally  some  giddiness  and  precordial  anxiety,  and  occasionally 
some  confusion  or  even  delirium  preceding  the  collapse. 

In  mammals  poisoned  with  colchicine,  the  alimentary  canal  exhibits 
all  the  appearances  of  acute  gastro-enteritis,  with  numerous  ecchymoses 
especially  in  the  upper  part  of  the  bowel.  In  less  acute  cases  these 
inflammatory  symptoms  are  less  marked,  and  in  man  there  is  seldom 
more  than  catarrh  of  the  duodenum. 

The  Circulation  is  but  little  affected  apparently.  In  animals  the 
blood-pressure  and  heart  rhythm  remain  normal,  and  though  a  small, 
rapid  pulse  may  be  one  of  the  features  of  the  poisoning  in  man,  this 
is  due  to  the  collapse  rather  than  to  any  direct  action  on  the  circula- 
tory organs. 

The  Respiration  is  slow,  but  is  deep  and  full  at  first.  Later  it  be- 
comes shallow,  and  the  failure  of  the  centre  is  the  cause  of  death,  the 
heart  continuing  to  beat  for  some  time  afterwards. 

The  Movements  of  the  Bowel  are  much  hastened  when  the  symptoms 
set  in,  and  Jacobj  believes  that  this  is  due  to  an  increase  in  the  irrita- 
bility of  the  nervous  mechanism,  which  accordingly  reacts  more  strongly 
than  usual  to  the  natural  stimuli ;  but  this  is  entirely  inadequate  to 
explain  the  acute  inflammatory  appearances,  which  are  evidently  due 
to  an  irritant  action  on  the  mucous  membrane. 

When  Locally  Applied  to  sensitive  mucous  membranes,  or  when  in- 
jected hypodermically,  colchicine  is  intensely  irritating,  producing 
redness  and  prickling  in  the  skin,  and  a  burning  sensation  in  the 
mouth  and  throat. 

The  Nervous  Symptoms  are  supposed  by  some  to  be  due  to  a  direct 
action  on  the  central  nervous  system,  but  may  probably  be  ascribed 
rather  to  a  condition  of  collapse  produced  indirectly  through  the  action 
on  the  abdominal  organs.  It  is  true  that  in  many  cases,  especially  in 
man,  the  post-mortem  appearances  do  not  indicate  any  marked  alter- 
ation of  the  stomach  and  intestine,  but  the  symptoms  throughout  in- 
dicate that  the  nervous  effects  are  indirect  in  their  origin,  and  not  due 
to  any  direct  depression  of  the  brain  cells.  When  the  collapse  symp- 
toms appear,  a  certain  degree  of  insensibility  to  external  impulses  may 
be  made  out  in  the  integument,  but  this  seems  due  rather  to  the  gen- 
eral depression  than  to  any  real  anaesthesia  of  the  skin. 

The  influence  of  colchicine  on  the  Kidneys  varies,  for  in  some  cases 
complete  anuria  is  produced  for  many  hours,  while  in  others  the  urine 


COLCHICINE.  345 

is  slightly  increased.  The  constituents  of  the  urine  are  not  materially 
altered  by  ordinary  therapeutic  doses  of  colchicum,  and,  in  particular, 
the  uric  acid  shows  no  constant  change  in  amount.  In  animals  bloody 
urine  is  sometimes  passed  after  colchicine. 

All  of  those  symptoms  are  exactly  those  caused  by  a  large  number 
of  poisons,  including  some  of  the  bacterial  toxines  and  the  heavy 
metals.  Many  local  irritants  when  injected  into  the  blood  or  when 
absorbed  from  the  subcutaneous  tissue  or  the  alimentary  canal,  exercise 
an  immediate,  local  action,  which  betrays  itself  in  pain,  or  ecchymosis 
and  swelling  at  the  point  of  injection,  but  these  symptoms  pass  off  in 
a  short  time  and  the  animal  becomes  apparently  normal  for  many 
hours  or  even  days.  At  the  end  of  this  time,  however,  symptoms  be- 
gin to  develop  at  two  points — -in  the  alimentary  canal  and  in  the 
kidneys.  The  reason  probably  is  that  the  poisons  are  excreted  at 
these  points  and  are  either  freed  from  some  harmless  combination  in 
which  they  have  circulated  in  the  tissues,  or  perhaps  collect  in  larger 
quantities  in  the  excretory  organs.  At  any  rate,  irritation  and  later 
acute  inflammation  are  set  up  at  these  points.  At  first  the  irritation 
excites  only  diarrhoea  and  diuresis,  but  as  it  goes  on  gastro-enteritis 
and  anuria  or  hsematuria  may  be  produced.  The  symptoms  from  the 
intestine  and  kidney  may  not  be  equally  well  marked  ;  at  one  time 
the  one  becomes  inflamed  while  the  other  is  only  subjected  to  mild 
stimulation,  while  at  other  times  both  are  the  seat  of  acute  inflamma- 
tion. The  inflammation  of  the  bowel  produces  a  condition  of  collapse, 
which  is  seen  also  in  various  intestinal  diseases,  such  as  cholera. 
Sometimes  the  poisons  (and  also  cholera)  produce  no  very  marked 
symptoms  of  gastro-intestinal  disorder,  but  rather  those  of  collapse, 
but  there  is  no  reason  to  believe  that  the  collapse  is  due  to  any  direct 
action  on  the  central  nervous  system. 

In  the  frog,  colchicine  has  little  or  no  effect,  but  if  the  solution  be  exposed 
for  some  time  to  the  air,  it  causes  a  prolongation  of  the  muscular  contraction 
similar  to  that  seen  after  veratrine,  and  eventually  a  tetanus  resembling  that 
due  to  strychnine.  Jacobj  therefore  believes  that  in  mammals  the  effects 
are  not  produced  by  colchicine  itself,  but  by  a  substance  formed  by  its  oxida- 
tion in  the  tissues,  oxydicolchicine.  The  frog's  tissues  are  unable  to  oxidize 
colchicine,  but  if  oxydicolchicine  be  formed  by  the  exposure  of  colchicine 
to  the  air,  it  produces  these  symptoms.  Oxydicolchicine  causes  the  same 
symptoms  in  mammals  as  colchicine. 

PREPARATIONS. 

Colchici  Cormus  (U.  S.  P.,  B.  P.),  the  corm  or  bulb  of  Colchicum  autumnale, 
0.1-0.3G.  (2-5  grs.). 

Extractum  Colchici  Cormi  (U.  S.  P.),  0.03-0.1  G.  (J-2  grs.). 

Extractum  Colchici  (B.  P.),  £-1  gr. 

VINUM  COLCHICI  (B.  P.)  (10-30  mins.). 

Colchici  Semen  (U.  S.  P.),  Colchici  Semina  (B.  P.),  the  seed  of  Colchicum 
autumnale. 

Fluidextractum  Colchici  Seminis  (U.  S.  P.),  0.1-0.3  c.c.  (2-5  mins.). 

Tinctura  Colchici  Seminis  (U.  S.  P.),  0.3-1  c.c.  (5-15  mins.). 

Tincfura  Colchici  Seminum  (B.  P.),  0.3-1  c.c.  (5-15  mins.). 

Vinum  Colchici  Seminis  (U.  S.  P.),  2-5  c.c. 


346  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

The  Vinum  Colchici  Radicis  is  the  preparation  usually  prescribed. 

Colchicina  (U.  S.  P.)  (C22H25NO6),  an  alkaloid  obtained  from  colchicum,  pale 
yellow  in  color,  with  a  bitter  taste  and  characteristic  odor ;  soluble  in  22  parts 
of  water  and  in  alcohol.  Dose,  0.5  mg.  (T£n  gr.). 

Therapeutic  Uses.  —  Colchicum  has  long  been  used  in  gout  on  purely 
empirical  grounds.  In  fact,  the  pathology  of  gout  is  so  obscure  that 
no  rational  treatment  for  it  can  be  looked  for  at  the  present  day,  and 
the  efficacy  of  colchicum  in  this  disease  can,  therefore,  be  argued  solely 
from  clinical  experience,  which  here  gives  only  uncertain  indications. 
Up  to  a  few  years  ago  the  routine  treatment  was  wine  of  colchicum, 
but  of  late  many  physicians  have  denied  that  any  benefit  whatso- 
ever was  obtained  from  its  use.  Others  maintain  that  colchicum  is 
at  any  rate  the  most  efficacious  drug  available  in  many  cases,  and  here 
the  matter  stands,  but  the  use  of  colchicum  in  gout  is  not  universal 
now,  as  it  was  formerly.  Some  attempt  has  been  made  to  place  the 
practice  on  a  rational  basis  by  showing  that  it  increased  the  excretion 
of  uric  acid.  But  a  number  of  other  intestinal  irritants  have  the  same 
effect,  and  it  now  seems  to  be  proved  that  gout  is  not  due  to  a  deficient 
excretion  of  uric  acid,  so  that  its  increased  elimination  would  not  ex- 
plain the  alleged  beneficial  effects  of  colchicum.  Besides  this  increase 
in  the  uric  acid  excretion  is  by  no  means  a  constant  result  of  colchicum 
medication,  for  it  not  infrequently  has  the  opposite  effect.  And  in 
gout  the  uric  acid  excretion  does  not  seem  to  be  modified  at  all  by  col- 
chicum. 

Colchicum  has  also  been  used  in  chronic  rheumatism  but  here  it  is 
of  little  or  no  benefit. 

BIBLIOGRAPHY. 

Jacobj.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii.,  p.  119. 

N.  Paton.  Brit.  Med.  Journ.,  1886,  i.,  p.  377,  and  Journ.  of  Anat.  u.  Phys. ,  xx., 
p.  267. 

Fawcett.     Guy's  Hospital  Reports,  lii.,  p.  115. 


XX.  SAPONIN,  SAPOTOXIN  AND  SOLANINE. 

Under  this  group  are  arranged  a  number  of  glucosides  which  have 
many  features  in  common  both  in  their  chemical  properties  and  in  their 
pharmacological  action.  Many  of  them  have  not  yet  been  completely 
isolated,  and  it  seems  not  unlikely  that  several  which  are  now  believed 
to  be  distinct,  will  prove  to  be  identical.  Robert  has  found  that  many 
of  them  may  be  arranged  in  a  chemical  series  CnH2n_8O10.  Some  have 
an  acid  reaction  and  form  salts  with  the  alkalies,  while  all  possess  the 
characteristic  glucosidal  reaction,  being  decomposed  by  acids  and  fer- 
ments into  sugars  and  unknown  inactive  substances.  The  most  poi- 
sonous among  them  are  designated  by  the  general  term  of  Sapotoxins, 
while  Saponin  may  be  used  to  include  the  less  active  ones  and  certain 
innocuous  isomers  of  the  sapotoxins  which  are  formed  from  them  by 
boiling  with  alkalies.  These  terms  as  well  as  the  popular  names  of 
several  of  the  plants  from  which  the  active  principles  are  derived, 


SAPOXIN,   SAPOTOX1N  AND  SOLANINE.  347 

refer  to  the  property  they  possess  of  forming  frothy,  soap-like  solutions 
in  water  and  of  holding  insoluble  bodies  in  suspension  in  it.  Very 
often  several  of  these  bodies  are  found  in  a  single  plant,  either  several 
powerfully  poisonous  ones  (sapotoxins),  a  mixture  of  sapotoxins  and 
saponins,  or  saponins  only. 

Saponins  or  sapotoxins  are  found  in  about  150  species  of  plants. 
The  chief  of  these  are : 

Quillaja  saponaria,  or  soapbark  (containing  quillaja-sapotoxm  and 
quillajac  acid). 

Saponaria  officinalis,  or  soapwort  (saporubrin  and  saponiri). 

Cyclamen  Europeum,  or  sowbread  (cyclamiri). 

Poly  gala  senega  (senegin  and  polygoMc  acid). 

Agrostemma  githago,  or  corncockle  (agrostemma-sapotoxin). 

Gypsophila  struthium  and  other  species  (gypsophila-sapotoxin). 

Chamaelirium  luteum,  or  blazing  star  (chamcelirium-sapotoxin). 

Smilax,  various  species,  including  those  known  as  sarsaparilla  (sarsa- 
ponin,  sarsapanlla-saponin  and  parillin  or  smilacin). 

In  addition  to  the  plants,  which  owe  their  action  to '  the  presence 
of  these  bodies,  a  number  of  drugs  contain  saponins  along  with  other 
more  important  principles.  Thus,  an  almost  inactive  saponin  (digi- 
tonin)  is  met  with  in  digitalis,  and  similar  saponins  probably  occur  in 
several  others  of  the  digitalis  series  although  they  have  not  yet  been 
isolated. 

The  most  poisonous  of  these  are  the  sapotoxins  of  quillaja,  agros- 
temma  and  gypsophila,  quillajac  acid,  and  cyclarnin.  Senegin  is  only 
about  one  tenth  as  poisonous  as  quillaja-sapotoxin,  and  the  saponins 
prepared  from  the  sapotoxins  are  still  less  dangerous. 

Another  body  closely  resembling  the  saponins  in  action  is  Solanine, 
a  glucosidal  alkaloid  found  in  many  species  of  Solanum,  such  as  S. 
nigrum  (black  nightshade),  S.  dulcamara  (bittersweet),  S.  tuberosum 
(potato),  and  probably  in  some  species  of  Scopolia.  In  Solanum  nigrum 
and  S.  dulcamara  it  is  accompanied  by  small  quantities  of  one  or  more 
bases  resembling  atropine,  while  in  dulcamara  a  glucosidal  body,  Dul- 
camarin,  has  been  found  also  belonging  to  the  sapotoxin  series. 
Solanine  is  said  to  be  generally  accompanied  by  Solaneine,  a  nearly 
related  alkaloid.  Solanine  breaks  up  on  being  heated  with  acids  into 
sugar  and  a  base,  Solanidine,  which  retains  the  poisonous  action.  In 
some  plants  both  solanine  and  solanidine  seem  to  be  present. 

Its  chief  importance  arises  from  its  occurrence  in  the  potato,  which 
has  given  rise  to  widespread  poisoning  in  several  instances.  The 
amount  of  solanine  in  the  potato  is  in  general  too  small  to  provoke 
poisonous  symptoms,  even  when  enormous  quantities  are  eaten,  but 
when  the  potatoes  begin  to  sprout  in  damp  cellars,  the  percentage  of 
solanine  rapidly  increases,  especially  in  the  green  buds  and  the  small 
young  tubers.  In  old,  rotting  potatoes  it  may  also  become  dangerously 
high,  but  cases  of  poisoning  are  more  likely  to  arise  from  the  use  of 
the  green,  unripe  potatoes  than  from  those  which  are  obviously  unfit 
for  use.  Weil  states  that  the  increase  in  solanine  seen  in  potatoes  that 


348  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

have  been  kept  too  long  is  due  to  the  presence  of  bacteria  which  form 
this  alkaloid  from  the  potato. 

In  any  case  the  potato  skins  contain  nearly  half  of  the  solanine, 
and  if  these  be  removed  before  boiling,  a  considerable  part  of  the 
alkaloid  contained  in  the  edible  part  is  extracted  by  the  water. 

Action.  —  The  sapotoxins  possess  a  very  irritant,  local  action,  and 
produce  acute  inflammation  of  the  alimentary  canal  and  extravasa- 
tions in  various  organs,  when  they  are  carried  to  them  by  the  blood. 
They  also  destroy  the  red  blood  cells  when  brought  into  contact  with 
them. 

They  have  a  harsh,  acrid,  unpleasant  taste,  and  when  swallowed  pro- 
voke nausea  and  often  vomiting,  with  pain  and  colic,  and  less  frequently 
diarrhoaa.  They  are  not  absorbed  by  the  normal  epithelium  of  the 
alimentary  canal,  and  therefore  fail  to  produce  general  symptoms,  un- 
less some  lesion,  such  as  gastric  ulcer,  is  present.  Thus  pigs  feed 
with  avidity  on  Cyclamen  and  are  unharmed  by  it  unless  some  lesion 
of  the  intestine  is  present.  The  unbroken  skin  is  not  affected  by  a 
single  application  as  a  general  rule,  and  absorption  is  extremely  slow 
from  the  subcutaneous  tissues,  in  which  they  act  as  irritants,  however, 
and  produce  inflammation  and  suppuration.  The  sapotoxin  derived 
from  Agrostemma  differs  from  the  others  in  being  absorbed  fairly 
rapidly  from  the  alimentary  canal  and  from  the  subcutaneous  tissues, 
so  that  more  dangerous  symptoms  may  arise  from  it  than  from  the 
other  members  of  the  series. 

In  an  epidemic  of  solanine  poisoning  from  potatoes  described  by 
Schmiedeberg,  the  symptoms  consisted  of  headache,  colic,  vomiting 
and  diarrhoea,  general  depression  and  weakness,  and  some  mental  con- 
fusion. In  severe  cases  pallor  or  cyanosis,  dilated  pupils,  short  periods 
of  unconsciousness  with  acceleration  and  then  slowing  of  the  pulse 
were  observed.  All  the  patients  recovered  in  the  course  of  ten  days. 
In  many  cases  some  rise  of  temperature  was  noted.  In  experiments 
on  animals,  Perles  found  almost  the  same  symptoms  and  the  same 
post-mortem  appearances  as  after  sapotoxin.  Diarrhoea  was  not  so 
easily  induced  by  solanine  as  by  the  poisonous  potato,  perhaps  because 
the  pure  poison  was  absorbed  from  the  stomach,  while  it  was  carried 
into  the  bowel  when  mixed  with  the  other  constituents  of  the  potato. 
Solanine,  on  the  other  hand,  seems  more  liable  to  cause  nephritis  than 
most  sapotoxins,  and  albumin  and  haemoglobin  are  generally  found  in 
the  urine.  When  solanine  is  administered  by  the  mouth,  most  of  it  is 
decomposed  in  the  tissues,  for  very  little  reappears  in  the  stools  and 
urine  as  solanine  and  solanidine. 

When  these  bodies  are  injected  directly  into  the  blood  vessels,  they 
induce  much  more  characteristic  changes,  which  very  often  prove  fatal 
after  a  longer  or  shorter  interval.  Very  large  quantities  thus  injected 
may  kill  animals  within  a  few  minutes  from  respiratory  paralysis,  and 
no  characteristic  appearances  are  to  be  found  post  mortem.  Smaller 
doses  induce  depression,  loss  of  appetite,  sometimes  vomiting  and  diar- 
rhoea, general  weakness  and  collapse,  with  some  dyspnoea  and  irregular, 


SAPONIN,  SAPOTOXIN  AND  SOLANINE.  349 

feeble  pulse.  Weak  convulsions  appear  just  before  the  failure  of  the 
respiration,  while  the  heart  continues  to  contract  for  some  minutes 
longer.  In  these  cases  ecchymoses  are  found  in  the  serous  membranes, 
pericardium,  pleura  and  peritoneum,  and  occasionally  in  the  kidneys. 
Endocarditis  has  been  observed  in  some  instances,  but  the  most  impor- 
tant alterations  occur  in  the  stomach  and  intestines,  the  mucous  mem- 
brane of  which  is  swollen  and  congested  and  contains  numerous  blood 
extravasations.  The  lymphatic  glands  of  the  abdominal  cavity  are 
also  swollen  and  congested  and  often  filled  with  haemorrhages.  Oc- 
casionally the  kidneys  are  found  to  contain  numerous  blood  casts  fill- 
ing the  lumen  of  the  tubules,  and  in  these  cases  albumin  and  hemo- 
globin appear  in  the  urine  before  death.  In  Cyclamen  poisoning 
(from  intravenous  injection)  haemoglobinuria  is  one  of  the  earliest 
symptoms. 

The  saponin  bodies  are  general  protoplasmic  poisons,  destroying  life 
wherever  they  come  in  contact  with  living  tissues  in  sufficient  concentra- 
tion. Their  irritant  action  on  the  mouth,  throat,  and  stomach  is  the 
cause  of  the  nausea  and  vomiting  observed  when  they  are  administered 
in  this  way,  and  they  cause  sneezing  and  coughing  from  the  same  action 
in  the  nose  and  throat.  On  other  mucous  membranes,  such  as  the  con- 
junctiva, and  in  wounds,  they  cause  similar  irritation  and  inflamma- 
tion, which  may  be  followed  by  suppuration.  A  form  of  local  anaes- 
thesia often  follows  this  irritation,  the  terminations  of  the  sensory 
nerves  apparently  being  benumbed,  but  the  preliminary  irritation  pre- 
cludes their  use  for  this  purpose. 

Even  the  unbroken  skin  may  be  irritated  when  they  are  applied  re- 
peatedly or  rubbed  on  in  the  form  of  ointment.  This  irritation  is  be- 
trayed by  redness,  heat,  itching,  and  eventually  by  the  formation  of 
pustules.  Their  local  effects  when  injected  subcutaneously  also  indi- 
cate their  irritant  properties. 

When  the  individual  organs  are  exposed  to  the  action  of  saponin 
bodies  by  the  direct  application  of  solutions  to  them,  a  similar  poison- 
ous action  is  elicited.  Muscle  contracts  more  weakly  even  in  dilute 
solutions,  is  eventually  entirely  paralyzed,  and  is  altered  in  structure, 
the  transverse  striae  of  voluntary  muscle  and  of  the  heart  becoming 
very  indistinct.  Nerves  exposed  to  solutions  are  also  paralyzed  in  the 
same  way,  and  the  movements  of  cilia  cease  at  once  when  they  are  ex- 
posed to  sapotoxin  bodies.  The  blood  undergoes  characteristic  changes 
when  it  is  acted  on  by  saponin  either  in  the  vessels  or  in  the  test-tube. 
The  coagulation  is  said  to  be  accelerated  by  small  quantities  of  cycla- 
min,  and  is  certainly  retarded  by  larger,  but  the  most  striking  effect  is 
the  destruction  of  the  red  corpuscles  and  the  liberation  of  the  haem- 
oglobin, which  forms  "  laky  "  blood.  Even  one  part  of  cyclamin 
added  to  100,000  parts  of  diluted  blood  completely  destroys  the  red 
blood  cells,  while  haemoglobin  appears  in  the  serum  when  consider- 
ably less  poison  is  added.  The  other  saponin  bodies  act  less  power- 
fully in  this  direction  than  cyclamin,  but  still  produce  distinct  solution 


350  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

of  the  substance  of  the  red  corpuscles.  When  a  saponin  is  injected 
into  the  blood  of  a  living  animal  this  destruction  of  the  red  blood- 
cells  takes  place  to  some  extent,  and  the  plasma  contains  haemoglobin, 
while  the  blood  corpuscles  are  considerably  diminished  in  number. 
This  haemolytic  action  is  not  the  result  of  changes  in  the  haemo- 
globin, for  the  corpuscles  are  found  to  be  more  permeable  by  salts 
also,  and  this  even  under  conditions  which  prevent  the  liberation  of 
haemoglobin  (Stewart) ;  it  has  recently  been  shown  that  saponin  acts 
more  powerfully  on  the  red  blood-corpuscles  in  the  absence  of  serum, 
and  that  the  stromata  of  the  corpuscles  are  the  parts  affected  and  not 
the  haemoglobin ;  finally,  it  appears  extremely  probable  that  the  haemol- 
ysis is  due  to  the  affinity  of  saponin  for  the  cholesterin  and  other 
lipoids  of  the  corpuscles,  the  changes  in  the  physical  condition  of  the 
cholesterin  through  the  permeation  of  the  glucoside  resulting  in  the 
rupture  of  the  cell  and  the  liberation  of  the  haemoglobin.  The 
serum  retards  the  action  of  saponin  on  the  corpuscles  by  fixing 
some  of  it  in  combination  with  its  lipoid  constituents  (Ransom, 
Hedon). 

The  circulation  in  mammals  is  comparatively  little  aifected  until 
just  before  death,  when  the  blood-pressure  falls  rapidly  and  the 
pulse  becomes  weak  and  slow.  The  heart  continues  to  beat  for 
a  short  time  after  the  respiration  ceases,  but  is  very  weak,  and  finally 
stops,  even  although  artificial  respiration  is  maintained.  The  isolated 
frog's  heart  is  paralyzed  by  sapotoxins  in  the  same  way  as  the  isolated 
muscle. 

In  many  experiments,  death  would  seem  to  be  caused  by  collapse  fol- 
lowing the  changes  in  the  alimentary  canal.  In  others,  however,  when 
only  small  quantities  of  the  poison  have  been  injected,  no  such  changes 
are  observed,  but  the  animal  dies  after  a  few  days,  presenting  no  dis- 
tinct symptoms  except  general  weakness  and  depression.  On  the 
other  hand,  very  large  quantities  injected  into  a  vein  may  prove  fatal 
within  a  few  minutes,  and  here  again  no  symptoms  of  intestinal  action 
may  appear.  It  is  therefore  believed  that  in  addition  to  their  irritant 
effects  these  bodies  have  a  special  action  on  the  central  nervous  system, 
although  it  is  impossible  at  present  to  specify  its  nature.  The  respira- 
tion is  in  all  cases  the  first  vital  function  to  be  suspended.  Sapotoxin 
applied  directly  to  the  spinal  cord  in  the  frog  first  provokes  convulsive 
twitching  and  clonic  spasms  and  then  paralyzes  the  animal,  but  it  may 
be  questioned  whether  it  would  have  the  same  effect  when  carried  in 
the  blood. 

The  sapotoxins  are  poisonous  to  invertebrates  apparently,  unless  they 
are  protected  by  a  shell,  through  which  they  can  not  penetrate.  Thus 
the  amoeba  and  other  simple  organisms  cease  their  movements,  while 
intestinal  worms  are  first  excited  and  then  paralyzed  in  the  presence 
of  some  of  the  group. 


SAPONIN,  SAPOTOXIN  AND  SOLANINE.  351 

PREPARATIONS. 

ftuillaja  (U.  S.  P.),  ftuillaiae  Cortex  (B.  P.),  Panama  bark,  Soap  bark,  the 
inner  bark  of  Quillaja  saponaria. 

Fluidextractum  Quillajce  (U.  S.  P.),  0.2  c.c.  (3  mins.). 

Tinctura  Quillajce  (U.S.  P.),  Tinctura  Quillaice  (B.  P.),  2-4  c.c.  (30-60  mins.). 

Sarsaparilla  (U.  S.  P.),  the  root  of  Smilax  ofiicmalis,  S.  medica,  S.  papy- 
racea  and  of  other  species  of  Smilax. 

Fluidextractum  Sarsaparilla?  (U.  S.  P.),  4  c.c.  (1  fl.  dr.). 

Fluidextractum  Sarsaparillce  Compositum  contains  sassafras,  liquorice,  and  meze- 
reum.  4  c.c.  (1  fl.  dr.). 

Syrupus  Sarsaparitlce  Compositus  (U.  S.  P.)  contains  liquorice,  senna,  and 
the  oils  of  sassafras,  anise  and  wintergreen.  10-15  c.c.  (2-4  fl.  drs. ). 

Sarsae  Radix  (B.  P.),  sarsaparilla,  the  dried  root  of  Smilax  ornata,  im- 
ported from  Costa  Eica  and  known  as  Jamaica  sarsaparilla. 

Liquor  Sarsoe  Compositus  Concentratus  (B.  P.)  is  formed  from  sarsaparilla,  sas- 
safras root,  guaiacum  wood,  liquorice  and  mezereum.  2-8  fl.  drs. 

Extractum  Sarsa?  Liquidum  (B.  P.),  2-4  fl.  drs. 

Senega  (U.  S.  P.),  Senegse  Radix  (B.  P.),  the  root  of  Polygala  Senega. 

Fluidextractum  Senega?  (U.  S.  P.),  0.5-1  c.c.  (10-15  mins.). 

Syrupus   Senega  (U.  S.  P.),  4-8  c.c.  (1-2  fl.  drs.). 

Tinctura  Senegce  (B.  P.),  £-1  fl.  dr. 

Liquor  Senegas  Concentratus  (B.  P.),  ^-1  fl.  dr. 

Infusum  Senega?  (B.  P.),  ^-1  fl.  oz. ;  as  a  draught,  2  fl.  oz. 

Hemidesmi  Radix  (B.  P.),  the  dried  root  of  Hemidesmus  Indicus. 

Syrupus  Hemidesmi  (B.  P.),  J-l  fl.  dr. 

Therapeutic  Uses. — The  drugs  of  this  group  are  all  quite  superfluous. 
They  may  be  used  to  increase  the  bronchial  secretion  in  cough  through 
the  nausea  caused  by  their  slight  irritant  action  in  the  stomach,  but  they 
have  no  advantages  over  such  drugs  as  ipecacuanha  or  apomorphine ; 
the  syrup  of  senega  is  often  prescribed  in  expectorant  mixtures  for 
this  purpose.  Sarsaparilla  has  been  supposed  to  have  an  obscure 
action  on  the  nutrition,  and  has  some  reputation  in  the  treatment  of 
syphilis,  but  there  is  no  reason  to  believe  that  it  is  of  any  service  here 
or  in  any  other  condition,  although  it  may  be  used  as  a  vehicle  for  the 
administration  of  mercury  and  iodide  of  potassium.  For  this  purpose 
the  compound  syrup  U.  S.  P.  or  compound  liquor  B.  P.  is  the  best 
preparation.  Quillaja  has  been  used  to  some  extent  as  an  expectorant, 
more  largely  to  form  emulsions  and  to  suspend  insoluble  powders.  Its 
poisonous  action  ought,  however,  to  preclude  its  use  for  this  purpose. 
It  is  frequently  stated  that  members  of  the  sapotoxin  series  are  anti- 
dotes in  digitalis  poisoning  ;  but  this  is  founded  on  experiments  in  which 
both  drugs  were  applied  directly  to  the  frog's  heart,  and  there  is  no  rea- 
son to  suppose  that  they  would  oppose  each  other  in  man,  especially  if 
given  by  the  mouth,  as  sapotoxin  is  absorbed  only  with  great  difficulty. 

Dulcamara  has  been  used  to  a  limited  extent  as  a  sedative  and  hyp- 
notic and  also  as  a  diuretic  and  diaphoretic  and  in  some  skin  diseases. 
It  does  not  seem  to  possess  any  properties  which  would  render  it  of 
value  in  medicine,  and  might  well  be  dispensed  with. 

Another  series  of  bodies  resembling  the  saponin  series  in  their  effects  are 
known  as  Solvines,  Oleites,  Polysolve,  etc.,  and  are  derived  from  oleic  and 
other  similar  acids  by  the  action  of  sulphuric  acid.  The  best  known  is  that 
formed  from  ricinoleic  acid.  According  to  Kiwull,  solvines  have  the  same 


352  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

destructive  action  as  sapotoxin.  They  have  been  used  in  medicine  to  form 
emulsions,  but  their  use  here  is  to  be  deprecated  on  the  same  grounds  as  that 
of  quillaja. 

BIBLIOGRAPHY. 

Robert.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiii.,  p.  233. 

Stewart.     Journ.  of  Exp.  Med.,  vi.,  p.  257 ;  Journ.  Med.  Research,  viii.,  p.  268. 
Hedon.     Arch,  internat.  de  Pharmacodyn.,  viii.,  p.  381 ;  ix.,  p.  393. 
Rartsom.    Deutsch.  med.  Woch.,  1901,  p.  194. 

Pachorukow,  Atlass  u.  Tufanow.     Arbeiten  a.  d.  Pharm.  Inst.  zu  Dorpat,  i. 
Kruskal.     Ibid.,  vi.,  p.  1. 
Kiwull     Ibid.,  iii.,  p.  1.     (Solvin.) 
SchuLz.     Ibid.,  xiv.,  p.  1. 

Bruere.     Journ.  of  Med.  Research,  viii.,  p.  362. 
Solanine. 

Husemann  u.  Balmanya.     Arch.  f.  exp.  Path.  u.  Pharm.,  iv.,  p.  309. 

Perks.     Ibid.,  xxvi.,  p.  88. 

Meyer  u.  Schmiedeberg.     Ibid.,  xxxvi.,  p.  361. 

P/uhL     Deutsch.  med.  Woch.,  1899,  p.  753. 

Weil.     Arch.  f.  Hygiene,  xxxviii.,  p.  330. 

XXI.     ASPIDOSPERMA,  OR  QUEBRACHO. 

The  bark  of  Quebracho  bianco  (Aspidosperma  quebracho)  contains  a  num- 
ber of  alkalojds  which  are  probably  very  similar  in  chemical  composition  and 
which  seem  to  possess  almost  the  same  action.  They  are  Aspidospermine, 
Aspidospermatine,  Aspidosamine,  Hypoquebrachine,  Quebrachine  and  Quebracha- 
mine.  Another  species  of  Aspidosperma,  Payta,  contains  two  alkaloids,  Pay- 
tine  and  Paytanine,  of  which  Paytine  resembles  closely  the  Quebracho  alka- 
loids in  its  pharmacological  action. 

These  alkaloids  all  produce  nausea  but  even  after  large  doses  vomiting 
does  not  occur  except  after  Aspidosamine.  The  nausea  is  accompanied  by 
the  usual  concomitant  symptoms — salivation,  increased  secretion  of  mucus 
in  the  respiratory  tract,  depression  and  alternately  rapid  and  slow  pulse. 
Large  quantities  often  cause  symptoms  of  central  nervous  stimulation,  tonic 
contractions  and  convulsions.  The  respiration  is  quicker  and  deeper  after 
small  quantities,  but  after  lethal  doses  becomes  slow  and  weak,  and  finally 
ceases.  Periodic  respiration  often  occurs  before  the  final  standstill,  a  series 
of  deep  dyspnoeic  movements  alternating  with  several  shallow,  insufficient 
ones.  The  failure  of  the  respiration  is  the  cause  of  death  in  mammals,  the 
heart  continuing  to^  contract  for  some  time  longer.  After  Aspidosamine, 
there  is  no  stage  of  quick  and  deep  respirations,  but  the  breathing  is  rendered 
slow  at  once  and  soon  becomes  periodic. 

These  symptoms  are  generally  ascribed  to  a  direct  action  on  the  central 
nervous  system,  which  is  first  stimulated  and  then  depressed.  The  chief 
seat  of  action  seems  to  be  the  medullary  centres  and  the  spinal  cord,  although 
the  basal  ganglia  may  also  be  more  or  less  involved.  The  stimulation  of  the 
medullary  centres  explains  the  nausea  and  vomiting  and  also  the  changes  in 
the  respiration,  while  the  convulsions  and  increased  reflex  excitability  point 
to  the  spinal  cord. 

The  terminations  of  the  motor  nerves  in  voluntary  muscles  are  paralyzed 
by  aspidosamine  and  quebrachine  in  the  frog,  not  by  the  other  alkaloids  ;  but 
all  of  them  lessen  the  strength  of  muscular  tissue  and  eventually  paralyze  it 
in  these  animals.  Neither  of  these  results  has  been  observed  to  follow  the 
injection  of  the  alkaloids  in  mammals. 

The  circulation  in  mammals  is  atiected  indirectly  through  the  nausea,  and 
the  heart  may  be  slowed  by  very  large  doses.  Wood  states  that  even  moderate 
quantities  reduce  the  blood-pressure  in  the  dog. 

Eloy  and  Huchard  observed  diarrhoea  and  an  increased  secretion  of  urine 
occasionally  follow  the  administration  of  the  alkaloids,  and  they  also  describe 


QUININE.  353 

a  curious  coloration  of  the  blood  which  they  ascribe  to  a  diminution  of  the 
haemoglobin.  Penzoldt  attributed  the  asphyxia  to  changes  in  the  red  cells, 
but  the  subject  of  the  action  of  these  alkaloids  on  the  blood  requires  further 
investigation. 

None  of  the  quebracho  alkaloids  is  very  poisonous,  but  of  the  series  que- 
brachine  is  the  most  toxic,  and  aspidosamine  and  aspidospermatine  follow  it 
closely.  Aspidospermine,  quebrachamine  and  hypoquebrachamine  are  com- 
paratively weak. 

Commercial  ' '  aspidospermine "  is  a  mixture  of  all  the  alkaloids  along 
with  other  bodies.  It  is  sometimes  prescribed  in  doses  of  1-2  mgs.  (fa-yv  gr.). 

Aspidosperma  was  advised  by  Penzoldt  in  the  treatment  of  dyspnoea  from 
a  variety  of  causes,  and  his  statements  have  received  a  certain  amount  of 
support  from  clinicians.  The  special  conditions  in  which  it  has  been  advised 
are  dyspnoea  from  pulmonary  disease,  especially  emphysema,  and  from  car- 
diac weakness  and  asthma.  Its  action  on  the  respiratory  centre  may  ex- 
plain to  some  extent  the  benefits  derived  from  it,  but  the  increased  secretion 
of  the  bronchi  produced  by  the  nausea  may  also  be  of  some  importance. 

It  has  also  been  employed  as  an  antipyretic,  and  has  been  shown  by  Eloy 
and  Huchard  to  lower  the  temperature  in  animals. 

BIBLIOGRAPHY. 

Harnacku.  Hoffman.     Zeitschr.  f.  klin.  Med.,  viii.,  p.  471. 
Eloy  u.  Huchard.     Arch,  de  Phys.  [3],  vii.,  1886,  p.  236. 
Gutmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiv.,  p.  451. 
Wood.    Univ.  of  Pennsylvania  Med.  Bull.,  Sept.,  1903. 

XXII.     QUININE. 

The  barks  of  various  species  of  Cinchona  and  Remijia  (Cuprea)  con- 
tain numerous  alkaloids  which  seem  to  resemble  each  other  closely  in 
their  chemical  and  pharmacological  properties.  The  best  known  of 
these  are  Quinine,  Quinidim,  or  Conquinine,  Cinchonijie  and  Cinchoni- 
dine;  the  others,  amounting  to  some  twenty  in  number,  are  believed 
to  resemble  these  in  their  effects  on  the  organism,  but  very  little  has 
been  done  to  determine  this,  and  nothing  is  known  regarding  their 
relative  activity. 

The  cinchona  alkaloids  are  derivatives  of  quinoline.  Cinchonine 
and  cinchonidine  are  isomeric  (C19H221S"2O)  and  perhaps  contain  two 
quinoline  molecules,  while  quinine  and  quinidine  (C20H94N2O2)  are 
methoxyl  compounds  of  cinchonine.1 

Cinchona  bark  contains  besides  these  alkaloids  several  acids,  includ- 
ing tannins,  and  some  neutral  substances. 

The  cinchonas  are  natives  of  Western  South  America,  but  are  now 
cultivated  in  India  and  Java.  It  seems  questionable  whether  the  vir- 
tues of  the  bark  were  known  by  the  native  Indians  before  the  invasion 
of  the  Spanish,  and  its  introduction  into  medicine  dates  from  about 
1630-1640  ;  its  name  bears  testimony  to  its  efficacy  in  the  case  of  the 
Countess  of  Chinchon  in  1638. 

1  The  other  alkaloids  of  this  series  which  have  been  identified  are  homocinchonidine, 
conquinamine,  quinamine,  cusconine,  concusconine,  aricine,  cusconidine,  cuscamine, 
cuscamidine,  hydroquinine,  hydroquinidine,  hydrocinchonine,  cinchonamine,  quaira- 
mine,  conquairamine,  quairamidine  and  conquairamidine,  while  several  others  are 
said  to  have  been  separated  by  some  authorities,  but  are  rejected  by  others.  The  acids 
generally  acknowledged  to  be  present  in  cinchona  are  quinic,  quinovic,  quinotannic, 
quinovatannic,  caffeotannic  and  oxalic,  while  the  neutral  bitter  substances  have  been 
named  quinovin,  quinova-red  and  cinchona-red. 
23 


354  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Action. — Quinine  differs  from  most  of  the  other  important  alkaloids 
in  acting  not  on  some  specialized  form  of  living  matter,  but  on  the  gen- 
eral nutrition  of  almost  all  forms  of  protoplasm.  Other  alkaloids,  such 
as  strychnine,  are  also  possessed  of  similar  effects  as  regards  nutrition, 
but  their  strong  affinity  for,  and  intense  action  on  some  special  tissue, 
prevent  their  effects  on  the  fundamental  (properties  of  living  matter 
from  being  elicited  in  the  higher  animals.  Quinine  is  therefore  often 
termed  a  protoplasm  poison  because  its  action  extends  with  but  little 
variation  throughout  most  forms  of  living  matter ;  on  the  other  hand 
the  marked  effect  of  strychnine  on  the  nerve  cell  causes  it  to  be  classed 
among  nerve  poisons,  although  in  organisms  devoid  of  a  nervous  sys- 
tem it  resembles  quinine  in  its  effects.  The  effects  of  quinine  on  pro- 
toplasm generally  consist  in  transitory  augmentation  of  its  activity, 
followed  by  depression  and  death. 

The  action  of  quinine  on  Undifferentiated  Protoplasm,  such  as  is 
found  in  the  unicellular  organisms  and  in  the  ovum,  is  therefore  of 
greater  interest  than  that  of  most  alkaloids.  Binz  found  that  while 
very  minute  quantities  sometimes  increase  the  movements  of  the  amoaba 
and  infusoria  at  first,  large  amounts  paralyze  them  immediately,  and 
the  protoplasm  assumes  a  darker  granular  appearance.  The  rhythmic 
movements  of  ciliated  organisms  are  rendered  slow  and  finally  arrested 
by  very  dilute  solutions.  The  microbes  of  putrefaction  are  also  acted 
upon  by  quinine,  although  they  seem  more  resistant  than  the  protozoa  ; 
still,  quinine  solutions  have  considerable  antiseptic  power,  equalling 
that  of  carbolic  acid,  according  to  some  observers.  The  alcoholic, 
lactic  and  butyric  fermentations  are  retarded,  or  entirely  prevented 
by  quinine  through  its  effects  on  the  organisms,  but  it  is  apparently 
devoid  of  action  on  some  of  the  lower  forms,  for  moulds  (Penicillium) 
grow  freely  in  solutions  of  the  salts  ;  so  that  the  alkaloid  seems  to  have 
a  selective  action  here,  such  as  is  observed  also  in  its  effects  on  the 
ferments  of  the  higher  animals.  Another  example  of  its  action  on  the 
vegetable  cell  is  that  discovered  by  Darwin  in  some  insectivorous 
plants  (Drosera),  in  which  the  movements  seem  to  be  first  excited  and 
later  paralyzed  by  the  quinine  salts. 

The  influence  of  quinine  on  the  reproductive  cells  of  animals  has 
been  carefully  studied  by  O.  and  R.  Hertwig,  who  found  that  both  the 
spermatozoon  and  the  ovum  of  the  sea-urchin  are  injured  by  the  addi- 
tion of  quinine  to  the  sea-water,  the  movements  of  the  former  being 
paralyzed,  and  the  stages  preceding  impregnation  in  the  latter  progress- 
ing more  slowly,  or  actually  retroceding.  When  quinine  is  applied 
after  the  male  nucleus  has  entered  the  ovum,  the  complete  conjugation 
is  delayed  and  the  whole  process  is  rendered  abnormal  by  the  admis- 
sion of  several  spermatozoa.  Quinine  applied  still  later  prevents  or 
delays  the  division  of  the  ovum  through  its  effects  both  on  the  nucleus 
and  on  the  general  protoplasm  of  the  cell. 

The  individual  cells  of  more  complex  organisms  are  affected  in  the 
same  way  as  these  more  simple  ones.  This  was  first  demonstrated  in 


QUININE.  355 

the  leucocytes  by  Binz,  and  after  some  opposition  has  been  generally 
accepted.  When  a  drop  of  blood  is  examined  under  the  microscope, 
the  white  cells  are  observed  undergoing  constant  changes  of  form  and 
position  exactly  similar  to  those  of  the  amreba,  but  minute  quantities 
of  a  quinine  salt  are  sufficient  to  stop  all  movements  at  once,  and  the 
leucocytes  assume  a  spherical  form,  become  darker  in  color  and  gran- 
ular, and  soon  break  up  into  debris.  In  the  blood  vessels  similar 
changes  occur  when  quinine  is  applied  locally,  as  to  the  frog's  mesen- 
tery ;  the  leucocytes  again  become  darkly  granular,  and  ceasing  their 
creeping  movements,  are  carried  along  by  the  current  much  more  rap- 
idly than  usual.  They  are  no  longer  observed  to  push  their  way  through 
the  vessel  walls,  and  if  they  have  already  penetrated  into  the  tissues 
their  movements  are  arrested.  If  irritation  be  applied  to  the  part,  no 
such  accumulation  of  leucocytes  occurs  in  the  tissues  as  in  the  unpoi- 
soned  animal,  and  if  an  irritant  has  been  applied  first  and  the  leuco- 
cytes have  poured  out  of  the  vessels  before  the  quinine  is  applied,  the 
process  is  arrested  at  once  on  its  application.  This  effect  was  explained 
by  Binz  as  due  to  the  poison  acting  on  the  leucocytes,  and  although 
attempts  have  been  made  to  explain  it  by  some  change  produced  on 
the  vessel  wall  by  the  drug,  there  now  seems  no  reason  to  question  the 
correctness  of  his  view.  Similar  results  are  observed  when  the  drug 
is  not  applied  locally,  but  carried  to  the  part  by  the  vessels  ;  the  move- 
ments of  the  leucocytes  in  the  vessels  are  less  distinct ;  they  are  carried 
along  passively  in  the  general  current,  assume  a  spherical  form,  and 
have  much  less  tendency  to  escape  into  the  general  tissues,  and  at  the 
same  time  the  number  of  the  leucocytes  in  the  blood  undergoes  a  con- 
siderable diminution.  It  would  be  unjustifiable  to  infer  from  these 
experiments  that  the  therapeutic  dose  of  quinine  inhibits  the  move- 
ments of  the  white  blood  cells  in  the  human  body,  and  it  is  no  part  of 
Binz's  theory  that  this  occurs.  The  effect  of  quinine  on  the  leucocytes 
is  merely  an  example  of  its  effects  on  the  tissues  generally.  At  the 
same  time,  the  number  of  leucocytes  in  the  human  blood  is  diminished 
by  ordinary  quantities  of  quinine,  showing  that  the  action  on  the  frog's 
leucocytes  extends  also  to  those  of  man,  even  when  the  quinine  is  ab- 
sorbed from  the  stomach  and  intestine. 

Other  evidence  of  the  action  of  quinine  is  gained  from  processes 
which  may  be  regarded  as  due  to  Unorganized  Ferments. 

Thus  the  oxidizing  action  of  drawn  blood  was  shown  to  be  dimin- 
ished in  several  experiments  performed  by  Binz.  Immediately  after 
its  issue  from  the  vessels  the  unpoisoned  blood  undergoes  a  diminution 
of  its  alkalinity,  from  the  oxidation  of  some  unknown  substances  at 
the  expense  of  the  oxyhsemoglobin,  which  is  partially  reduced.  This 
acid  fermentation  is  prevented  by  the  addition  of  quinine  to  the  blood. 
Even  when  pieces  of  tissues  are  added  and  the  reduction  of  the  arterial 
blood  would  ordinarily  be  much  accelerated,  quinine  prevents  or  retards 
the  change.  A  similar  inhibition  of  the  oxidizing  action  of  the  blood 
is  shown  by  its  failure  to  form  the  blue  oxidation  product  of  guaiac, 


356  ORGANIC  DRUG 'S  ACTING  AFTER  ABSORPTION. 

or  to  decolorize  indigo  when  it  is  applied  to  it  along  with  quinine.1 
Or  instead  of  blood  a  slice  of  potato  or  a  watery  extract  of  a  liv- 
ing plant  may  be  used.  From  these  experiments  the  inference  is 
drawn  that  quinine  hinders  the  action  of  the  oxidizing  ferment  of  the 
blood  and  tissues.  On  the  other  hand,  Jacquet  found  that  it  had  little 
or  no  effect  on  the  oxidation  of  substances  passed  through  the  vessels 
of  excised  organs.  Another  ferment  action  which  is  said  to  be  retarded 
by  the  presence  of  quinine  is  the  coagulation  of  the  blood.  The  gastric 
and  pancreatic  ferments  are  also  said  to  be  rendered  less  active  by  the 
addition  of  quinine  in  artificial  digestion  experiments  (Rossbach), 
while  the  ptyalin  of  the  saliva,  emulsin  and  diastase  are  unaffected 
(Binz). 

These  experiments  indicate  that  quinine  hinders  some,  if  not  all,  of 
the  processes  which  normally  occur  in  living  matter,  and  which  are 
expressed  in  movement  and  in  various  chemical  products ;  they  indi- 
cate in  addition  that  this  action  is  not  confined  to  the  intact  protoplasm, 
but  extends  to  some  of  the  ferments.  When  very  minute  quantities 
of  the  drug  are  applied,  the  stage  of  depression  is  sometimes  preceded 
by  one  of  augmented  activity.  Rossbach  found  that  quinine  and 
several  other  alkaloids  exercise  some  influence  on  solutions  of  the 
proteids,  which  coagulate  at  a  lower  temperature  than  usual,  but  it  is 
impossible  to  determine  at  present  whether  this  fact  is  connected  with 
their  effects  on  living  tissue  or  is  merely  a  coincidence. 

Among  the  Vertebrates,  also,  small  quantities  of  quinine  give  rise 
to  disturbances  of  the  nutrition,  but  before  discussing  these,  it  may 
be  well  to  indicate  the  symptoms  induced  by  poisonous  doses. 

In  the  frog,  a  short  stage  of  increased  reflex  excitability  is  followed  by 
the  loss  of  spontaneous  movements,  the  arrest  of  respiration  and  paralysis 
of  the  spinal  cord.  In  mammals,  the  spinal  cord  is  said  to  be  stimulated  by 
small  quantities  and  then  to  be  depressed.  The  respiration  is  sometimes 
accelerated  in  the  beginning,  but  is  afterwards  weakened,  and  its  failure  is 
the  cause  of  death.  General  depression  and  muscular  weakness  are  usually 
the  only  cerebral  effects  noted,  and  the  tremor  and  convulsions  said  to  occur 
in  some  instances  may  be  due  to  the  use  of  impure  quinine.  The  heart  is 
often  accelerated  at  first,  but  is  afterwards  slow  and  weak,  while  the  blood- 
pressure,  after  a  slight  increase,  declines  progressively.  According  to  ISan- 
tesson,  quinine  given  by  the  stomach  has  comparatively  little  effect  on  the 
heart  and  blood-pressure  in  mammals.  These  symptoms  point  to  a  prelimi- 
nary stage  of  stimulation,  followed  by  depression  of  the  Central  Nervous 
System  and  heart  in  the  vertebrates,  corresponding  to  the  two  stages  ob- 
served in  the  simpler  organisms.  They  are  only  elicited  by  very  large 
quantities  of  the  drug  and  have  perhaps  received  greater  attention  than  they 
merit  at  the  hands  of  experimental  pharmacologists.  The  depression  of  the 
reflexes  of  the  frog  was  at  one  time  attributed  to  a  stimulation  of  the  in- 
hibitory centres  of  Setschenow,  and  this  was  supported  by  the  fact  that  it 
could  be  removed  at  first  by  division  of  the  medulla  oblongata.  It  seems 

1  The  well-known  guaiac  experiment  is  performed  as  follows  :  A  fresh  solution  ol 
guaiac  resin  in  alcohol,  to  which  some  peroxide  of  hydrogen  has  been  added,  it 
divided  into  two  parts.  To  the  one  a  minute  quantity  of  quinine  is  added,  and  one  01 
two  drops  of  blood  are  then  allowed  to  flow  into  each  part.  The  one  containing  the 
quinine  remains  uncolored,  while  the  other  assumes  a  blue  tint  from  the  oxidation  oi 
the  guaiac  by  the  unpoisoned  blood. 


•     QUININE.  357 

more  probable,  however,  that  the  local  irritation  of  the  acid  salts  usually 
injected  caused  the  temporary  depression  indirectly,  and  that  the  action  on 
the  central  nervous  system  consists  in  a  transient  stimulation  followed  by 
lasting  depression.  The  statement  that  the  depression  is  due  to  the  weak- 
ness of  the  heart  seems  incorrect. 

The  changes  in  the  Circulation  in  mammals  are  caused  by  a  preliminary 
contraction  of  the  arterioles  and  acceleration  of  the  heart,  followed  by  dila- 
tion of  the  former  and  slowing  and  weakening  of  the  latter.  In  both  cases 
the  action  is  probably  a  direct  one  on  the  muscle  of  the  arterioles  and  heart, 
although  some  investigators  consider  the  acceleration  due  to  depression  of 
the  inhibitory  mechanism  in  the  heart  or  in  the  medulla  oblongata.  The 
effects  of  quinine  on  the  isolated  frog's  heart  have  been  studied  carefully  by 
Santesson,  who  found  that  the  action  was  entirely  muscular  and  consisted 
in  slowing,  accompanied  by  marked  decrease  in  the  strength  of  the  contrac- 
tions. 

In  fatal  poisoning  in  mammals  the  heart  is  generally  very  much  weakened 
when  the  respiration  ceases,  but  continues  to  beat  for  some  time  afterwards. 

Quinine  acts  upon  Muscle  in  the  same  way  as  upon  the  simple  organisms, 
temporarily  increasing  its  power  and  subsequently  weakening  it.  Thus 
Santesson  found  that  the  strength  of  the  individual  contractions  was  in- 
creased, and  that  a  contraction  occurred  against  greater  resistance  than 
normally,  but  when  the  stimulation  was  repeated,  fatigue  set  in  sooner  than 
in  the  unpoisoned  muscle.  Large  quantities  of  quinine  throw  the  muscle 
into  rigor,  which  resembles  that  produced  by  caffeine,  and  is  probably  asso- 
ciated with  its  action  in  accelerating  the  coagulation  of  myosin  (Fiirth). 

The  Nerve  Trunks  are  said  to  be  remarkably  tolerant  to  solutions  of  qui- 
nine, which  do  not  lessen  their  irritability  when  applied  locally  in  sufficient 
quantity  to  cause  marked  abnormalities  in  the  muscular  contraction.  No 
sufficient  evidence  has  been  brought  forward  that  quinine  affects  the  periph- 
eral ends  of  the  motor  or  sensory  nerves.  The  number  of  Leucocytes  in  the 
blood  is  much  diminished  by  the  administration  of  quinine  in  man  and  the 
lower  mammals,  but  it  is  unknown  how  this  is  effected.  The  statement  that 
the  normal  Spleen  undergoes  a  contraction  in  size  and  partial  atrophy  after 
quinine,  while  not  improbable  in  itself,  is  not  supported  by  experiments  in 
which  accurate  methods  were  used. 

A  slight  increase  in  the  amount  of  Urine  excreted  has  been  observed  some- 
times, but  does  not  seem  constant.  It  is  attributed  to  the  action  of  the  qui- 
nine on  the  renal  epithelium,  by  which  it  is  excreted.  The  other  secretions 
do  not  seem  to  be  altered  by  quinine  unless  it  is  applied  directly  to  the  cells 
in  large  quantity  by  injecting  solutions  into  the  duct  of  the  gland.  The 
statement  is  made  that  the  glycogenic  function  of  the  liver  is  altered  so  that 
less  sugar  than  usual  is  supplied  to  the  blood,  and  there  is  some  evidence 
that  other  hepatic  functions  are  less  active  than  usual. 

Cinchona  preparations  and  quinine  have  the  same  action  on  the  appe- 
tite and  digestion  in  man  as  the  simple  bitters  and  nux  vomica.  Or- 
dinary therapeutic  doses  often  produce  no  very  obvious  symptoms,  the 
most  frequently  observed  effect  consisting  in  derangement  of  the  Sense 
of  Hearing,  less  frequently  of  that  of  Sight.  Ringing  or  roaring  sounds 
in  the  ears,  accompanied  by  slight  deafness,  are  produced  by  moderate 
quantities  and  large  doses  are  not  infrequently  followed  by  complete 
loss  of  hearing  for  a  time.  Contraction  of  the  field  of  vision  is  ob- 
served less  often,  but  in  some  cases  total  blindness  has  been  produced 
and  has  lasted  for  several  days  or  even  weeks.  Color-vision  is  es- 
pecially liable  to  be  rendered  imperfect  or  temporarily  paralyzed  by 
quinine ;  these  disorders  of  sight  are  accompanied  by  a  very  marked 


358  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

contraction  and  even  obliteration  of  the  retinal  vessels  and  sometimes 
by  degenerative  changes  in  the  retinal  nerve-cells  and  even  by  atrophy 
of  the  optic  nerve.  It  is  still  undecided  whether  the  vascular  changes 
or  the  nervous  degeneration  is  the  primary  lesion,  but  the  majority  of 
investigators  at  present  favor  the  view  that  the  constriction  of  the  ves- 
sels is  merely  an  accompaniment  of  the  graver  effects  on  the  ganglionic 
structures.  The  symptoms  in  the  ear  have  generally  been  regarded  as 
the  result  of  congestion  and  haemorrhages  in  the  tympanum  and  laby- 
rinth, but  Wittmaack  has  recently  shown  that  this  view  is  founded  on 
erroneous  observations,  and  states  that  degenerative  changes  occur  in 
the  spiral  ganglion  in  the  cochlea  exactly  analogous  to  those  described 
in  the  retina.  Quinine  possesses  some  irritant  action  which  betrays 
itself  in  discomfort  in  the  stomach  and  eructation  after  large  and  re- 
peated doses  by  the  mouth,  and  by  pain  and  tenderness  when  it  is 
injected  subcutaneously ;  but  this  drawback  is  not  of  so  much  import- 
ance as  in  the  case  of  many  other  drugs. 

Large  doses  of  quinine  produce  some  confusion  and  depression  with 
a  sense  of  fulness  and  heaviness  in  the  head  from  their  action  on  the 
Cerebrum,  and  this  is  sometimes  accompanied  by  uncertain  gait  and 
slow  pulse.  Very  few  cases  of  fatal  poisoning  have  been  satisfactorily 
determined  to  be  due  to  quinine,  although  a  considerably  larger  num- 
ber have  been  attributed  to  it.  In  these  cases  marked  weakness  of  the 
heart  and  collapse  accompanied  by  loss  of  sight  and  hearing,  muscular 
weakness,  apathy,  slow,  gasping  respiration  and  finally  unconscious- 
ness and  total  failure  of  the  respiration  were  observed.  In  some  cases 
delirium  and  convulsions  have  been  noted,  but  it  may  be  doubted 
whether  the  preparation  did  not  contain  other  members  of  the  cin- 
chona alkaloids.  Enormous  doses  of  quinine  sulphate  have  been 
swallowed  without  any  serious  results.  Thus  in  one  case  thirty 
grammes  (one  ounce)  produced  only  some  confusion  and  noises  in  the 
ears.  Probably  only  a  small  quantity  of  the  drug  was  absorbed,  as 
the  sulphate,  which  is  generally  used,  is  exceedingly  insoluble. 

The  extensive  use  of  quinine  in  therapeutics  has  demonstrated  that 
many  persons  have  curious  Idiosyncrasies  in  regard  to  it.  This  is  be- 
trayed in  many  cases  by  the  development  of  ear  symptoms  after  com- 
paratively small  doses,  but  in  others  symptoms  arise  which  do  not 
appear  in  the  great  majority  of  people  even  after  large  doses.  The 
commonest  of  these  are  skin  eruptions,  of  which  a  large  variety  have 
been  described,  and  which  can  be  distinguished  from  ordinary  diseases 
of  the  skin  only  by  the  history  or  by  the  detection  of  quinine  in  the 
urine  and  other  excretions.  These  exanthemata  are  often  accompanied 
by  some  rise  in  temperature,  which  has  received  more  attention  than 
it  appears  to  deserve,  for  it  is  rare  and  even  when  present  is  of  insig- 
nificant extent.  Other  less  important  effects,  which  have  been  occa- 
sionally noted,  are  gastric  discomfort  and  diarrhoea.  In  very  rare  cases 
the  administration  of  quinine  is  followed  by  fever  and  hsemoglobinuria 
(black  water)  or  albuminuria  ;  the  patients  are  in  almost  every  case 


QUININE.  359 

sufferers  from  old  malarial  infection,  but  there  is  no  question  that  in 
many  cases  the  symptoms  arise  only  when  quinine  is  given. 

The  action  of  quinine  on  the  Uterus  is  the  subject  of  a  large  number 
of  memoirs,  but  is  still  quite  uncertain.  Abortion  certainly  occurs 
occasionally  after  its  use  in  malaria,  while  in  other  cases  labor  pains 
may  be  induced  by  quinine.  Many  physicians  use  it  during  labor  if 
the  pains  cease  or  if  they  seem  to  be  too  weak  to  expel  the  child.  But 
opinions  differ  as  to  its  efficiency,  for  while  some  regard  it  as  the  most 
useful  of  remedies  for  this  purpose,  others  have  found  it  to  fail  in  the 
great  majority  of  cases  and  regard  this  action  as  an  idiosyncrasy  con- 
fined to  a  small  proportion  of  individuals.  It  is  quite  impossible  to 
state  how  quinine  acts  here,  but  is  seems  most  likely  that  the  uterine 
muscle  is  affected  directly. 

In  the  Alimentary  Tract,  quinine  and  the  cinchona  preparations  act 
in  the  same  way  as  the  simple  bitters  (page  56).  Quinine  delays 
proteolysis  in  experiments  in  artificial  digestion. 

The  constant  effects  of  quinine  on  the  Metabolism,  which  are  pro- 
duced by  quantities  of  the  drug  too  small  to  have  any  further  action 
except  in  specially  susceptible  individuals,  are  of  much  greater  interest 
and  importance  than  the  symptoms  already  mentioned.  This  alteration 
of  the  tissue  change  occurs  throughout  the  mammalia,  and  consists  in  a 
marked  diminution  in  the  destruction  of  the  nitrogenous  constituents 
of  the  tissues.  After  the  administration  of  quinine,  the  nitrogen  in  the 
urine  is  found  at  first  slightly  augmented  for  a  few  hours,  but  then  un- 
dergoes a  diminution  of  considerable  extent,  due  to  a  restricted  produc- 
tion of  all  the  nitrogenous  constituents  of  the  urine,  but  especially  of  the 
urea  and  uric  acid.  The  phosphates  and  sulphates  undergo  a  corre- 
sponding alteration,  but  all  metabolic  changes  are  not  affected,  for 
the  carbonic  acid  exhaled  and  the  oxygen  absorbed  by  the  lungs  pre- 
sent no  marked  alteration  in  amount,  so  that  the  oxidation  of  the  tissues 
cannot  be  said  to  be  altered,  but  only  the  breaking  down  of  the  nitroge- 
nous bodies.  This  absence  of  effect  on  the  oxidation  of  the  body  is  not 
what  might  have  been  expected  from  the  experiments  of  Binz  and 
others  on  the  simpler  tissues,  for  these  showed  that  oxidation  of  all  kinds 
was  retarded  by  quinine.  On  the  other  hand,  it  corresponds  with  Jac- 
quet's  experiments  on  the  oxidizing  ferment  of  the  tissues,  and  has  been 
attested  by  too  many  observers  to  allow  of  any  doubt  as  to  its  correct- 
ness. In  the  case  of  several  other  drugs  the  diminution  of  the  urea  is 
compensated  for  by  the  increase  in  the  other  nitrogenous  bodies  in 
the  urine,  but  the  fall  in  the  total  excretion  of  nitrogen  after  quinine 
points  to  an  alteration  of  the  metabolism  of  the  body  in  general,  and 
not  to  the  paralysis  or  destruction  of  the  organs  which  change  the 
first  products  of  the  nitrogenous  metabolism  to  the  simpler  forms  in 
which  they  are  finally  excreted.  The  oxygen  absorbed  and  the  car- 
bonic acid  excreted  by  the  tissues  are  generally  held  to  measure  the 
amount  of  work  done  and  heat  formed  by  the  muscular  and  other 
movements  of  the  body,  and  quinine  therefore  does  not  seem  to  affect 
these  functions,  while  it  would  appear  that  some  other  processes,  per- 


360  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

haps  the  death,  growth  and  repair  of  the  tissues,  are  less  active  than 
normally.  At  any  rate  the  nitrogenous  food  is  not  dissipated  so  rap- 
idly, but  is  stored  up  in  the  body  in  some  unknown  form,  for  v.  Noorden 
found  that  under  constant  diet  the  nitrogen  excretion  diminished  under 
quinine  and  this  diminution  continued  for  two  days  after  the  treat- 
ment was  stopped.  The  nitrogen  absorbed  from  the  alimentary  canal 
remained  unchanged,  and  a  certain  amount  of  proteid  food  must  there- 
fore have  been  added  to  the  body  and  saved  from  the  decomposition 
which  it  would  have  undergone  in  ordinary  circumstances. 

The  influence  of  quinine  on  the  metabolism  is  closely  connected 
with  its  effects  on  the  body  Temperature.  It  was  early  observed  that 
besides  its  specific  effects  in  malaria,  quinine  often  depressed  the  tem- 
perature and  improved  the  condition  in  a  number  of  other  fevers.  This 
was  long  supposed  to  be  due  to  some  action  that  it  exercised  on  the 
central  nervous  system,  but  when  the  nervous  theory  of  fever  fell  into 
disrepute,  this  explanation  also  came  to  be  looked  upon  with  suspicion, 
and  was  finally  disposed  of  by  the  experiments  of  Binz  and  others,  who 
showed  that  quinine  lowered  the  fever  temperature  after  division  of 
the  spinal  cord.  Binz  therefore  attributed  the  antipyretic  effects  of 
quinine  to  its  direct  action  on  the  tissues,  and  this  explanation  is  gen- 
erally held  to  be  correct.  It  is  to  be  remarked  that  while  there  is  no 
question  as  to  the  reduction  of  the  temperature  effected  by  quinine  in 
many  cases  of  fever,  it  has  little  effect  upon  the  normal  temperature. 
In  some  cases  a  slight  fall  in  the  thermometer  is  observed,  but  it  is 
never  very  considerable,  and  often  no  results  follow  its  administration, 
or  a  rise  of  0.1— 0.2°  C.  may  occur. 

Gottlieb  found  that  the  fever  temperature  produced  in  rabbits  by 
injury  of  the  region  of  the  corpus  striatum  was  reduced  by  quinine,  and 
that  the  regulation  of  the  heat  production  according  to  the  temperature 
of  the  surrounding  air  was  not  impaired  by  it.  Thus,  when  the  tem- 
perature of  the  cage  was  kept  at  about  30-32°  C.,  and  animals  poisoned 
with  morphine  and  some  other  drugs  had  fever  temperature,  the  rab- 
bit to  which  quinine  had  been  administered,  showed  little  change  from 
the  normal.  From  this  he  infers  that  the  heat-regulating  mechanism 
of  the  brain  is  not  affected  by  quinine,  and  that  the  reduction  of  tem- 
perature, when  it  occurs  at  all,  is  due  to  alteration  in  the  metabolism. 
In  a  later  research  the  same  author  found  by  calorimetric  experiments 
that  the  warmth  production  was  lessened  by  quinine,  both  in  normal 
animals  and  in  those  in  which  fever  had  been  induced  by  injury  of  the 
corpus  striatum.  This  lessened  production  was  accompanied  in  Gott- 
lieb's experiments  by  a  fall  in  the  output  of  heat,  the  regulating  appa- 
ratus tending  to  counterbalance  the  reduced  formation  in  the  same 
way  as  in  normal  animals.  In  other  experiments,  however,  quinine 
has  been  found  to  induce  dilatation  of  the  skin  vessels  and  a  corre- 
sponding increase  in  the  heat  loss.  In  other  words,  quinine  appears  to 
lessen  the  heat  formation  through  its  action  on  the  tissues,  and  this  is 
sometimes  compensated  for  by  a  decrease  in  the  heat  loss,  but  in 
other  instances  the  regulation  fails  and  the  temperature  falls  from  the 


QUININE. 


361 


FIG. 


formation  being  lessened  and  the  loss  remaining  unchanged  or  even 
being  increased. 

This  explanation  of  the  antipyretic  effects  of  quinine  is  not  without 
difficulties,  however.  For  the  chief  source  of  heat  in  the  body  is  the 
oxidation  of  the  carbohydrates,  but  in  healthy  animals  quinine  does 
not  lessen  the  amount  of  carbonic 
acid  excreted,  as  it  might  be  ex- 
pected to  do  if  it  reduced  the  heat 
formation  by  restricting  the  com- 
bustion in  the  tissues.  Some 
writers,  therefore,  hold  that  the 
fall  in  temperature  is  really  the 
effect  of  dilatation  of  the  skin 
vessels  and  increased  heat  loss. 
This  explanation  is  not  that 
generally  accepted,  however,  and 
while  it  is  not  denied  that  the 
augmented  output  of  heat  may 
in  some  conditions  contribute  to 
the  fall  in  temperature,  the  anti- 
pyretic action  of  quinine  is  still 
regarded  as  due  for  the  most  part 
to  its  retarding  the  metabolism ; 
it  has  been  suggested  that  while 
the  combustion  in  the  normal 
tissues  is  not  affected  by  quinine, 
the  presence  of  fever  poisons 
throws  them  into  a  state  of  aug- 
mented activity  in  which  they 
are  more  susceptible  to  its  sed- 
ative action,  and  that  even  in 
the  normal  organism  a  reduction 
of  the  temperature  might  be  in- 
duced if  sufficient  of  the  drug 
other  symptoms. 


Diagram  to  illustrate  the  relation  of  the  warmth 
output  and  internal  temperature  (after  one  of  Gott- 
lieb's experiments).  The  unbroken  line  represents 
the  changes  in  the  warmth  output,  which  may  be 
estimated  by  measuring  its  distance  from  the  ab- 
scissa A B.  The  dotted  line  represents  the  internal 
temperature.  From  .4  to  H,  normal.  At  If  an  in- 
jury to  the  brain  caused  a  marked  diminution  in 
the  heat  output  and  a  corresponding  rise  in  the  in- 
ternal temperature.  At  Q  quinine  was  administered 
and  was  followed  by  an  immediate  fall  in  the  inter- 
nal temperature,  while  the  heat  output  was  practic- 
ally unchanged.  Contrast  Fig.  35. 


could  be  ingested  without  exciting 
In  this  connection  it  is  of  interest  to  remember  that 
in  fever  the  nitrogenous  decomposition  is  much  increased,  while  quinine 
has  a  directly  opposite  effect.  The  diminution  in  the  nitrogenous 
metabolism  may  also  lead  to  an  increased  resistance  being  offered  by 
the  tissues  to  the  cause  of  the  fever,  or  may  lessen  the  poisonous  pro- 
ducts circulating  in  the  blood.  In  addition,  the  microbes  of  fever  may 
themselves  be  rendered  less  active  by  the  drug,  although  this  antiseptic 
action  would  appear  to  be  of  subordinate  importance,  as  many  of  the 
pathogenic  forms  have  been  found  to  offer  great  resistance  to  it. 

Quinine  has  much  more  effect  in  reducing  temperature  when  it  is 
administered  in  the  beginning  of  a  natural  remission  than  when  it  is 
given  during  a  rise  of  the  thermometer.  This  property  is  shared  by 
most  antipyretics  and  will  be  treated  of  at  greater  length  under  the 
antipyrine  series. 


362  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Excretion. — Quinine  appears  in  the  urine  within  a  short  time  (30 
minutes)  after  its  exhibition  by  the  mouth,  and  about  one  half  of  the 
quantity  absorbed  is  excreted  within  six  hours.  After  this  it  passes 
out  of  the  body  more  slowly,  and  traces  may  be  detected  in  the  urine 
seventy-two  hours  after  its  administration.  In  some  fevers  the  ex- 
cretion is  said  to  be  considerably  retarded.  Kerner  found  that  some 
of  the  quinine  absorbed  was  partially  hydrated  in  the  tissues  and  ex- 
creted as  dihydroxyl-quinine,  but  if  any  such  change  occurs,  it  can 
affect  only  a  very  small  proportion  of  the  alkaloid,  as  over  ninety  per 
cent,  of  that  ingested  has  been  recovered  unaltered  from  the  urine.1 

Of  the  Other  Cinchona  Alkaloids,quinidme  or  conquinine  resembles  quinine 
most  closely  in  its  effects,  which  are  somewhat  weaker,  however.  Cincho- 
nine,  while  very  similar  to  quinidine  in  most  points,  has  some  tendency  to 
produce  convulsions,  but  this  effect  is  much  more  liable  to  occur  under  cin- 
chonidine  which  save  for  its  resemblance  in  other  features  to  quinine,  would 
be  entitled  to  be  classed  among  the  convulsive  poisons.  These  convulsions 
are  of  an  epileptiform  character,  and  are  only  produced  by  very  large  doses, 
but  Albertoni  discovered  that  even  small  quantities  administered  to  epilep- 
tics increased  the  number  of  the  attacks.  He  found  that  these  epileptiform 
seizures  were  not  prevented  by  the  removal  of  the  cerebral  cortex  in  dogs,  and 
that  the  irritability  of  the  motor  areas  was  not  altered  by  cinchonidine,  and 
therefore  concluded  that  the  poison  produced  these  symptoms  by  acting  on 
some  lower  division  of  the  central  nervous  axis.  It  is  believed  by  many, 
however,  that  epileptic  attacks  can  be  elicited  only  when  the  cerebral  cortex 
is  intact,  and  although  no  results  directly  opposed  to  those  of  Albertoni  have 
been  recorded,  the  question  must  still  be  regarded  as  an  open  one. 

In  other  respects  cinchonine  and  cinchonidine  differ  from  quinine  only  in 
the  degree  and  not  in  the  kind  of  their  action.  Cinchonamine  possesses  an 
even  more  marked  convulsant  action  than  cinchonidine. 

The  effects  of  the  other  alkaloids  have  not  been  the  subject  of  much  in- 
vestigation, but  they  seem  to  differ  from  quinine  chiefly  in  their  effects  on 
the  central  nervous  system.  These  are  not  entirely  absent  in  quinine  itself, 
for,  as  has  been  stated  already,  the  reflex  irritability  is  at  first  increased  and 
then  diminished  in  both  frogs  and  mammals,  and  in  some  cases  even  con- 
vulsions are  stated  to  have  occurred  in  quinine  poisoning,  although  these  are 
so  rare  that  the  suspicion  is  aroused  that  the  preparation  was  contaminated 
with  cinchonidine  or  some  other  alkaloid. 

Cinchonidine  seems  the  most  poisonous  of  the  four  chief  alkaloids,  quinine 
following  next,  and  then  cinchonine  and  quinidine. 

PREPARATIONS. 

U.  S.  P. — Cinchona,  the  bark  of  Cinchona  calisaya  and  of  C.  officinalis 
and  of  hybrids  of  these  and  of  other  species  of  Cinchona,  yielding  not  less 
than  5  per  cent,  of  total  alkaloids  and  at  least  2.5  per  cent,  of  quinine. 

Cinchona  Rubra,  red  cinchona,  the  bark  of  Cinchona  succirubra,  contain- 
ing at  least  5  per  cent,  of  alkaloids. 

Fluidextractum  Cinchonce,  4  c.c.  (1  fl.  dr.). 

TINCTURA  CINCHONA,  4-15  c.c.  (1-4  fl.  drs.). 

TINCTURA  CINCHONJE  CoMPOSiTA  is  the  only  preparation  of  red  cinchona, 
and  contains  in  addition  serpentaria  and  bitter  orange  peel.  4-15  c.c.  (1-4 
fl.  drs.). 

These  preparations  of  cinchona  were  formerly  much  more  in  vogue  than  at 
the  present  day,  in  which  they  have  been  replaced  for  most  purposes  by  the 

1  Further  investigation  regarding  the  fate  of  quinine  in  the  human  tissues  is  desir- 
able, since  Merkel  has  found  that  seven-eighths  of  that  administered  to  dogs  is  com- 
pletely oxidized  and  the  remaining  eighth  undergoes  extensive  chemical  change. 


QUININE.  363 

alkaloids.     They  are  still  prescribed  alone  or  together  with  other  remedies  as 
stomachic  bitters. 
QUININA, 

SULPHAS, 

0.3-1  G.  (5-15  grs.) ;  to  be  increased  when 
necessary. 


Quinince  Bimlphas, 
Quinince  Hydrobromidum, 


QUININE  HYDROCHLORIDUM, 

Quinince  Salicylas  (U.  S.  P.), 

Oleatum  Quinince  (U.  S.  P.), 

Ferri  et  Quinince  Citras,  0.3-0.6  G.  (5-10  grs.). 

Ferri  et  Quinince  Citras  Solubilis,  0.3-0.6  G.  (5-10  grs.). 

Syrupus  Ferri,  Quinince  et  Strychnince  Phosphatum,  Easton's  syrup,  4  c.c.  (1 
fl.  dr.). 

Cinchonince  Sulphas         j  Q ^  g  G    (8_20         }> 

Cinchomdince  sulphas,    j 

Elixir  Ferri,  Quinince  et  Strychnince  Phosphatum,  4  c.c.  (1  fl.  dr.). 

Glyceritum  Ferri,  Quinince  et  Strychnince  Phosphatum,  1  c.c.  (15  mins.). 

B.  p. Cinchona  Rubrae  Cortex,  red  cinchona  bark,  the  dried  bark  of  the 

stem  and  branches  of  Cinchona  succirubra.  It  ought  to  contain  5-6  per 
cent,  of  total  alkaloids,  of  which  one  half  should  consist  of  quinine  and  cin- 
chonidine. 

Extractum  Cinchonse  Liquidum,  5  per  cent,  of  alkaloids,  5-15  mins. 

TINCTURA  CINCHONA,  1  per  cent,  of  alkaloids,  |-1  fl.  dr. 

TINCTURA  CINCHONA  COMPOSITA,  containing  bitter  orange  peel,  serpen- 
tary  and  coloring  matters,  £-1  fl.  dr. 

Infusum  Cinchonse  Acidum,  containing  aromatic  sulphuric  acid,  ^-1  fl.  oz. 

QUININE  HYDBOCHLORIDUM,        1 

Quininse  Hydrochloridum  Acidum,  >  1-10  grs. 

QUININE  SULPHAS,  ) 

Tinctura  Qulninse,  formed  from  the  hydrochloride  and  flavored  with  orange, 
£-1  fl.  dr. 

Tinctura  Quininse  Ammoniata,  formed  from  the  sulphate,  J-l  fl.  dr. 

Vinum  Quininee,  J-l  fl.  oz. 

Pilula  Quininse  Sulphatis,  2-8  grs. 

Syrupus  Ferri  Phosphatis  cum  Quinina  et  Strychnina,  Easton's  syrup.  Each 
fl.  dr.  contains  i  gr.  of  quinine  sulphate  and  &  gr.  of  strychnine.  \-\  fl.  dr. 

Ferri  et  Quininse  Citras,  5-10  grs.     (See  Iron.) 

Quinine  is  practically  insoluble  in  water  and  several  of  its  salts  are  only  dis- 
solved sparingly.  Thus,  the  sulphate  requires  800  times  its  own  weight  of 
water,  the  hydrochlorate  35,  the  hydrobromate  54,  and  the  valerianate  100.  The 
presence  of  acid  in  excess  renders  them  much  more  soluble,  and  the  acid  hydro- 
chlorate  is  dissolved  in  less  than  its  own  weight  of  water,  the  bisulphate  in  10 
parts.  They  all  form  crystalline  powders  with  a  very  bitter  taste,  and  their 
solutions  in  water  have  a  blue  fluorescence  when  sulphuric  acid  is  present.  The 
acid  hydrochloride  and  the  bisulphate  have  an  acid  reaction,  the  others  are 
neutral. 

The  sulphate  of  quinine  is  the  salt  generally  prescribed,  although  the  hydro- 
chlorate  is  more  soluble  and  ought  to  be  preferred.  The  hydrobromate  and  vale- 
rianate are  comparatively  seldom  used.  Instead  of  the  acid  salts  being  pre- 
scribed, some  sulphuric  acid  or  hydrochloric  acid  may  be  ordered  to  be  added  to 
the  neutral  salts  in  order  to  facilitate  their  solution. 

The  salts  of  quinine  are  frequently  given  in  the  form  of  pills,  cachets,  tablets, 
or  capsules,  which  have  the  advantage  of  avoiding  the  bitter  taste,  but  from 
which  the  alkaloid  is  more  slowly  absorbed  than  from  solutions.  Care  must  be 
taken  that  the  pills  are  soft  and  freshly  prepared,  as  when  kept  for  any  length 
of  time  they  become  hard,  and  in  this  condition  frequently  pass  through  the 
bowel  unabsorbed.  The  salts  or  the  pure  alkaloid  may  also  be  given  as  powders, 
or  the  former  in  solution,  but  these  are  objected  to  by  many  patients  on  account 


364  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

of  the  bitter  taste.  When  a  rapid  absorption  is  desired,  solutions  should  be 
used,  flavored,  if  necessary,  with  syrup  and  volatile  oils.  Solutions  of  the  salts 
are  occasionally  injected  as  enemata,  but  are  liable  to  set  up  irritation  and  be 
rapidly  evacuated.  The  hypodermic  method  has  also  been  advised  in  cases  of 
emergency,  or  where  the  salt  cannot  be  retained  or  absorbed  from  the  stomach  ; 
for  this  purpose  a  solution  of  the  hydrochlorate  with  hydrochloric  acid  in  excess 
or  of  the  sulphate  is  injected  deeply  into  the  muscular  tissue.  This  form  of 
medication  is  painful,  but  does  not  seem  to  induce  more  serious  results  if  ordi- 
nary care  is  used.  The  neutral  hydrochlorate  may  be  dissolved  in  hot  water 
and  injected  when  the  solution  reaches  body  temperature  with  less  pain  than  is 
elicited  by  other  salts.  In  this  way  about  two  parts  of  water  are  required  to 
dissolve  one  of  quinine.  The  addition  of  urea  to  the  solution  renders  it  less 
irritant.  Quinine  is  very  easily  dissolved  in  water  when  it  is  mixed  with  anti- 
pyrine  in  the  proportion  of  three  parts  of  quinine  to  two  of  antipyrine,  and  this 
solution  is  said  to  be  less  painful  when  it  is  injected  hypodermically  than  others. 
The  intravenous  injection  of  quinine  has  been  practised  by  Baccelli  with  success 
in  cases  of  pernicious  malaria.  He  uses  the  hydrochlorate  in  a  solution  of  com- 
mon salt  and  injects  into  one  of  the  veins  of  the  arm. 

Many  other  salts  of  quinine  have  been  proposed,  and  have  enjoyed  a  certain 
reputation  for  some  time.  Among  the  better  known  of  these  is  the  tanna.te, 
which  is  exceedingly  insoluble  and  almost  tasteless,  and  is  prescribed  in  powder 
in  doses  of  1-3  G.  Other  salts  which  have  been  recommended  are  the  tar- 
trate  and  the  lactate.  Euquinine  is  the  ethyl-ether  of  quinine-carbonic  acid 
(CO(OC2H5)(OC20H23N2O))  and  is  said  to  possess  the  therapeutic  virtues  of  qui- 
nine without  its  bitter  taste  and  without  inducing  ringing  in  the  ears  and  other 
symptoms.  Aristochme  (CO(C20H23N2O)2)  and  Chinaphenine  (CO(NH-  C6H4-  OC2- 
H5)(OC20H23N2O))  are  compounds  of  quinine  of  a  similar  nature  recently  intro- 
duced. All  three  preparations  are  prescribed  in  powder  or  tablets,  in  the  same 
dose  as  quinine. 

A  famous  preparation  of  quinine  is  Warburg's  tincture,  which  has  been  exten- 
sively used  in  India  in  the  treatment  of  malaria.  It  contained  a  very  large 
number  of  ingredients,  many  of  which  were  certainly  entirely  superfluous. 
Among  the  more  important  constituents  were  aloes,  rhubarb,  gentian,  camphor, 
and  various  volatile  oils  ;  it  is  possible  that  some  of  these  may  have  aided  the 
quinine  through  their  effects  on  the  stomach.  Various  drugs,  such  as  capsicum 
and  piperine,  have  long  had  some  reputation  as  adjuvants  in  quinine  treatment 
for  a  similar  reason. 

The  other  alkaloids  have  been  used  occasionally  as  substitutes  for  quinine, 
but  have  somewhat  less  therapeutic  effect,  while  cinchonidine  is  more  liable  to 
produce  symptoms  of  poisoning.  They  might  all  be  dispensed  with,  without 
loss  to  therapeutics. 

Quinoidine  and  qulnetum  were  formerly  used  as  substitutes  for  quinine  at  a 
time  when  the  price  of  the  latter  was  very  high.  They  were  mixtures  of  the 
other  cinchona  alkaloids  and  have  fallen  into  disuse. 

Therapeutic  Uses.  —  The  introduction  of  cinchona  into  therapeutics 
was  due  to  the  discovery  of  its  efficacy  in  ague  or  Malaria,  and  with 
growing  experience  in  the  disease  and  its  treatment,  the  confidence  in 
the  drug,  or  rather  in  its  chief  alkaloid,  has  constantly  increased,  until 
the  action  of  quinine  in  malaria  is  now  quoted  as  the  best  example  of 
a  specific  in  therapeutics.  The  explanation  of  its  action  has  only  been 
arrived  at  within  the  last  few  years  with  the  discovery  of  the  cause  of 
malaria,  the  plasmodium  malarise,  although  in  1868  Binz  suggested 
that  the  then  unknown  malarial  poison  was  probably  rendered  inert  by 
quinine.  The  plasmodium  belongs  to  the  group  of  protozoa,  and  in 
one  of  its  stages  comes  to  resemble  somewhat  the  amoeba,  on  which 


QUININE. 


365 


Binz  experimented.  The  effect  of  quinine  seems  similar  in  the  two 
organisms,  although  it  is  probable  that  the  alkaloid  acts  more  strongly 
on  the  malarial  organism  in  the  blood  than  on  the  common  amoeba 
living  in  water ;  another  organism  closely  related  to  that  of  malaria 
and  found  in  the  blood  of  birds  appears  to  be  unaffected  by  quinine. 
When  quinine  is  administered  to  a  patient  suffering  from  malaria,  the 
organism  in  the  blood  breaks  up  and  disappears,  leaving  only  a  few 
more  resistant  forms  ;  these,  however,  may  continue  to  grow  and  mul- 
tiply until  they  cause  a  second  attack,  unless  the  treatment  be  continued 
and  the  surviving  organisms,  changing  into  less  resistant  forms,  are 
destroyed  by  the  drug. 

In  a  drop  of  malarial  blood  the  plasmodia  may  be  seen  in  active 
movement,  but  a  minute  drop  of  quinine  solution  paralyzes  and  kills 
them,  exactly  as  it  kills  the  amoeba.  The  explanation  of  the  action  of 
quinine  on  malaria  lies  in  its  effects  as  a  protoplasmic  poison,  therefore, 
which  acts  more  strongly  (specifically)  on  the  lower  forms  of  life  than 
on  the  higher,  and  can  consequently  be  introduced  into  the  human  body 
with  impunity  in  doses  which  are  destructive  to  the  simpler  organisms 

Fio.  34. 


BOOKS 

105' 


KU 


Temperature  chart  in  a  case  of  malaria  in  which  quinine  (10  grains)  was  administered  in  the  third 
paroxysm  as  the  temperature  was  falling.  On  the  following  day  no  rise  of  temperature  occurs. 
The  te'uiperature  was  taken  every  three  hours.  (DOCK.) 

which  may  have  invaded  it.  Experience  has  shown  that  quinine 
is  most  effective  when  it  can  act  immediately  after  the  paroxysms 
of  ague,  and  this  is  now  explained  by  the  fact  that  the  organisms  are 
in  their  least  resistant  form — the  amoeboid  —  at  this  time.  If  quinine 
is  given  at  the  beginning  of  an  attack,  sufficient  will  remain  in  the  blood 
when  the  temperature  begins  to  fall  to  destroy  the  unprotected  spores 
of  the  parasite,  or  the  same  result  may  be  obtained  by  a  dose  given  as 
the  temperature  begins  to  fall  provided  the  drug  is  rapidly  absorbed, 


366  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

as  is  ordinarily  the  case.  It  may  be  ordered  in  one  dose  of  about  1  G. 
(15  grs.),  or  in  divided  doses  given  at  intervals  during  the  fall  of  the 
temperature.  This  frequently  prevents  the  next  attack,  but  if  any  rise 
of  temperature  occurs,  a  smaller  dose  should  be  administered.  After 
this  a  dose  of  1  G.  should  be  given  every  six  days,  in  order  to  com- 
plete the  destruction  of  the  organisms  which  have  developed  from  the 
resistant  forms  left  alive  after  the  first  administration.  Quinine  is 
generally  administered  by  the  mouth  in  malaria,  but  its  intensely  bitter 
taste  renders  this  treatment  disagreeable,  and  in  children  and  in  cases 
of  persistent  vomiting  it  may  be  impossible ;  in  such  circumstances  it 
may  be  given  in  an  enema  or  suppository,  or  in  children  the  tasteless 
forms  may  be  employed.  In  recent  years  good  results  have  been  ob- 
tained by  the  hypodermic  method,  and  in  the  severe  form  known  as 
pernicious  malaria,  Baccelli  found  the  intravenous  injection  superior 
to  any  other  method  of  administration.  A  great  deal  of  weight  was 
formerly  laid  on  the  use  of  purgatives  and  emetics  as  preliminaries  to 
the  treatment  of  malaria  with  quinine,  and  the  former  are  undoubtedly 
of  service  sometimes,  although  it  is  unnecessary  to  delay  the  quinine 
treatment  by  waiting  for  the  intestines  to  be  evacuated. 

Quinine  is  used  not  only  as  a  remedy,  but  also  as  a  prophylactic 
against  malaria.  Its  value  for  this  purpose  has  been  attested  by  long 
experience,  but  there  is  still  no  unanimity  of  opinion  as  to  the  best 
method  of  administration  and  the  dose  required.  Plehn  found  that 
one  gramme  of  the  sulphate  given  in  one  dose  every  seven  days  was 
sufficient  to  prevent  the  disease,  which  is  believed  to  have  an  incuba- 
tion period  of  a  week,  while  others  recommend  doses  of  0.1-0.2  G. 
(2-3  grs.)  every  morning. 

One  of  the  results  of  quinine  medication  in  early  cases  of  malaria  is 
the  reduction  of  the  enlarged  spleen,  and  this  has  led  to  its  use  in 
other  Diseases  of  the  Spleen  with  enlargement.  In  malaria  the  effect 
on  the  spleen  is  only  secondary  to  the  removal  of  the  cause  of  the  dis- 
ease, but  the  action  of  quinine  in  lessening  the  number  of  leucocytes 
in  the  blood  might  explain  some  alteration  in  the  spleen.  In  some 
cases  of  leucsemic  enlargement  encouraging  results  have  been  obtained 
from  the  continued  use  of  quinine. 

Various  other  Febrile  Conditions  have  been  treated  with  quinine, 
partly  for  the  sake  of  its  antipyretic  effects  and  partly  in  the  belief 
that  it  acts  as  an  antiseptic  in  the  blood.  As  regards  its  effect  on  the 
temperature  in  non-malarial  fever,  it  not  infrequently  causes  a  con- 
siderable fall,  and  has  the  advantage  of  possessing  a  more  prolonged 
action  and  of  causing  less  risk  of  depression  and  collapse  than  the  newer 
antipyretics.  On  the  other  hand,  the  fever  is  not  reduced  so  rapidly 
and  generally  not  to  the  same  extent  as  by  the  latter,  and  the  large 
quantities  of  quinine  required  are  liable  to  cause  discomfort  from  their 
effects  on  the  brain  and  hearing.  Typhoid  fever,  scarlatina  and  other 
acute  pyrexias  are  sometimes  treated  with  quinine  for  this  effect.  The 
best  results  are  obtained  when  it  is  exhibited  in  maximal  doses  when 
the  temperature  is  falling  or  when  it  has  been  temporarily  reduced  by 


QUININE.  367 

other  means,  such  as  cold  baths.  Perhaps,  however,  the  beneficial  ac- 
tion of  quinine  in  those  cases  ought  to  be  measured  not  so  much  by 
the  reduction  of  the  body  temperature  as  by  the  lessened  destruction 
of  the  tissues.  It  would  be  interesting  to  know  whether  in  those 
cases  in  which  quinine  treatment  is  successful,  the  nitrogen  of  the  urine 
is  diminished  in  proportion  to,  or  in  excess  of  the  fall  of  the  tempera- 
ture. In  general,  antipyrine  and  its  allies  have  succeeded  in  ousting 
quinine  from  its  former  position  as  the  best  of  the  antipyretics.  The 
use  of  quinine  has  been  recommended  in  septicaemia,  largely  from  a 
belief  in  its  antiseptic  action  in  the  blood.  In  this  connection  it  is  to 
be  remarked  that  the  microbes  of  septic  fever  are  very  much  more 
resistant  to  the  action  of  quinine  outside  the  body  than  are  the  pro- 
tozoa, and  the  question  therefore  arises  whether  the  blood  and  tissues 
are  not  liable  to  be  seriously  injured  by  the  quantity  of  quinine  re- 
quired to  act  on  the  parasites  they  contain.  In  many  cases  of  septi- 
ca3mia  in  which  beneficial  results  are  said  to  have  been  obtained  by  the 
use  of  quinine,  the  quantity  administered  was  obviously  too  small  to 
have  any  effect  either  on  the  temperature  or  on  the  microbes. 

Quinine  has  been  used  in  various  forms  of  Neuralgia  and  Headache, 
especially  when  they  were  periodic  in  their  appearance,  and  good  re- 
sults nave  been  obtained  in  these  cases  and  also  in  others  where  no 
periodicity  could  be  observed.  Many  of  these  were  certainly  not  of 
malarial  origin,  and  no  explanation  of  the  action  of  quinine  here  has 
been  proposed.  Perhaps  the  lessened  formation  of  uric  acid  and  other 
poisonous  products  may  be  suggested  as  a  possible  cause  of  the  im- 
provement. 

The  tinctures  of  cinchona  are  often  prescribed  as  stomachic  bitters 
and  for  .this  purpose  are  generally  fortified  by  preparations  of  nux 
vomica  or  of  the  simple  bitters. 

Quinine  has  been  advised  in  whooping-cough,  hay  fever  and  in- 
fluenza, and  in  fact  is  regarded  by  many  as  a  specific  in  these  diseases, 
though  others  have  found  it  unreliable.  It  is  often  difficult  to  induce 
a  child  to  take  the  bitter  salts,  and  recourse  may  be  had  to  the  alka- 
loid itself,  euquinine,  or  the  tannate  disguised  with  sugar  or  chocolate. 
The  use  of  a  solution  as  a  wash  for  the  nose  in  hay  fever  was  brought 
into  prominence  by  Helmholtz,  who  gained  relief  in  this  way,  but 
it  has  not  proved  very  efficacious.  The  local  use  of  quinine  solu- 
tions and  of  cinchona  preparations  is  also  advised  in  relaxed  throat 
(gargle)  and  in  gonorrhoea  (urethral  injection).  It  has  sometimes 
been  used  as  an  antiseptic  externally,  but  is  too  expensive  for  ordi- 
nary use. 

Quinine  has  been  advised  as  an  ecbolic  to  increase  the  contractions 
of  the  uterus  during  labor.  This  was  suggested  by  the  observation 
that  in  malarial  regions,  abortion  occasionally  occurred  after  quinine, 
but  many  regard  this  as  one  of  the  rarer  idiosyncrasies  rather  than  as 
a  fact  upon  which  the  therapeutic  use  of  the  drug  is  to  be  based.  At 
the  same  time  others  report  the  most  satisfactory  results  from  the 
treatment  of  uterine  inertia  with  one-gramme  doses  of  quinine,  and  pre- 


368  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

fer  it  to  ergot  in  this  condition.     The  movements  of  the  uterus  induced 
are  said  to  be  practically  identical  with  those  occurring  naturally. 

Contraindications. — Where  a  special  idiosyncrasy  exists,  quinine  may 
be  unsuitable,  but  these  cases  are  far  rarer  than  is  generally  believed. 
A  moderate  action  on  the  hearing,  for  example,  is  not  to  be  considered 
a  contraindication,  although  in  those  cases  a  small  dose  is  often  found 
sufficient  in  malaria.  Where  an  inflammatory  condition  of  the  mem- 
branes of  the  ear  already  exists,  quinine  ought  to  be  administered  with 
care,  or  avoided  entirely  if  possible.  The  addition  of  bromides  is 
often  found  to  lessen  or  remove  the  discomfort  arising  from  the  dis- 
ordered hearing,  but  the  quantity  of  bromide  contained  in  the  hydro- 
bromate  of  quinine  is  insufficient  to  effect  this,  and  the  ordinary  potas- 
sium salt  ought  therefore  to  be  prescribed.  Where  very  marked 
disturbance  of  the  digestion  exists,  quinine  is  often  liable  to  augment  it, 
owing  to  its  irritant  properties,  and  must  therefore  be  given  with  cau- 
tion by  the  mouth,  or  perhaps,  is  better  applied  hypodermically. 
Ha3moglobinuria  following  the  administration  of  quinine,  of  course, 
contraindicates  its  further  use.  Abortion  so  seldom  occurs  after  qui- 
nine that  pregnancy  is  no  objection  to  its  administration.  In  general, 
it  may  be  stated  that  quinine  is  often  credited  with  many  disadvan- 
tages which  it  does  not  possess,  and  that  in  cases  of  malaria,  in  which 
it  is  practically  without  a  rival  or  substitute,  only  the  most  pronounced 
idiosyncrasy  can  justify  withholding  it.  In  other  cases,  as  in  septic 
fever,  it  may  be  a  question  whether  it  does  not  aggravate  the  condition 
when  it  is  administered  to  very  weak  patients. 
i 

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ACETANILIDE  AND  ANTIPYRINE  SERIES.  369 

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XXIII.    THE  ANTIPYRETICS.    (ACETANILIDE  AND 
ANTIPYRINE    SERIES.) 

The  antipyretics  are  a  very  recent  addition  to  therapeutics,  the  old- 
est of  this  group  now  in  use  dating  only  from  1884.  Up  to  1875  the 
only  means  of  combating  high  temperature  were  baths,  vegetable  alka- 
loids such  as  quinine  and  aconitine,  or  alcoholic  preparations,  but  in 
that  year  Buss  discovered  that  salicylic  acid  produced  a  fall  in  the  fever 
temperature,  and  soon  afterward  carbolic  acid  and  resorcin  and  its 
isomers  were  introduced  as  antipyretics.  A  very  large  number  of 
antipyretics  have  been  introduced  since  that  time,  but  most  of  them 
have  had  only  a  temporary  vogue,  and  those  in  general  use  at  the 
present  time  are  comparatively  limited  in  number. 

Quinine  is  a  quinoline  derivative,  and  quinoline  itself,  as  well  as  some  of  its 
simpler  compounds,  were  among  the  earlier  antipyretics  suggested.  Quinoline 
(C9H7N)  was  soon  found  to  be  dangerous  from  its  producing  collapse,  but  its 
derivatives  Kairine  (C9H9(OH)N  —  C^,  Kairoline  (C9Hg(CH3)(OH)NH)  and 
Thalline  (C9H9(OCH3)NH)  were  used  extensively,  although  they  have  now  been 
almost  entirely  abandoned.  In  fact  the  only  quinoline  bodies  now  used  as 
antipyretics  are  Analgen  and  Thermifugine,  which  are  still  prescribed  to  a  lim- 
ited extent. 

A  new  antipyretic  was  introduced  in  1884  under  the  name  of  Antipyrine, 
which  is  derived  from  phenylhydrazine,  and  has  proved  superior  to  all  of  the 
earlier  drugs.  Phenylhydrazine  (C6H5  —  NH  —  NH2)  produces  a  fall  in  the 
fever  temperature,  but  this  is  frequently  accompanied  by  collapse  and  changes 
in  the  blood,  which  prevents  its  use  in  medicine.  Several  of  the  simpler  com- 
pounds, such  as  Pyrodine  (acetylphenylhydrazine)  and  Antithermine  (phenyl- 
hydrazine and  Isevulinic  acid),  have  received  a  more  or  less  extensive  trial  as 
antipyretics,  but  have  proved  dangerous  and  inferior  to  Antipyrine,  phenyl- 

dimethylpyrazolon,    C6H5  -  N  <^°H^_~  ^^ '•     The  latter  is  still  very 

largely  used  as  an  antipyretic,  either  in  its  original  form  or  as  a  constituent 
of  numerous  combinations  which  have  been  introduced  of  late  years.  Among 
these  may  be  mentioned  Resopyrine  (resorcin  and  antipyrine),  Hypnal  (chloral 
and  antipyrine),  Salipyrine  (salicylic  acid  and  antipyrine). 

Antipyrine  early  found  a  rival  in  Antifebrine  or  Acetanilide,  which  was 
advised  as  an  antipyretic  in  1886  by  Cahn  and  Hepp.  Aniline  (C6H5NH2), 
from  which  it  is  derived,  has  also  some  action  on  the  temperature,  but  like 
phenylhydrazine  producer  dangerous  collapse  and  destruction  of  the  blood 
cells.  Acetanilide  (C6H5NHCOCH3),  the  first  of  its  derivatives  to  be  intro- 
duced, is  not  entirely  devoid  of  this  poisonous  action,  and  has  been  supplanted 
to  a  considerable  extent  by  more  complex  and  less  poisonous  bodies.  One  of 
these,  Exalgine  (C6H5NCH3COCHS),  differs  from  antifebrine  only  in  possessing 
a  methyl  group  in  the  side  chain,  and  seems  to  resemble  it  closely  in  its  effects. 
Another  which  enjoyed  a  short  trial  is  Benzanilide  (C6H5NHC7H5O),  in  which 
the  acetyl  radicle  of  antifebrine  is  replaced  by  benzoyl.  It  was  soon  found 
that  both  aniline  and  antifebrine  underwent  a  partial  oxidation  in  the  body, 
24 


370  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

with  the  formation  of  amidophenol  or  its  derivatives,  and  the  belief  that  the 
antipyretic  effects  were  due  not  so  much  to  the  original  substance  as  to  these 
oxidation  products  led  to  the  introduction  of  numerous  derivatives  of  par- 

amidophenol    l^e-^i^^jj  )•     ^his  body  has  antipyretic  properties  but  suffers 

under  the  same  disadvantages  as  aniline.  Among  its  derivatives  the  most  sat- 
isfactory antipyretics  are  those  in  which  the  hydrogen  of  the  hydroxyl  is  sub- 
stituted by  an  alkyl,  while  an  acid  radicle  is  added  to  the  amido-radicle.  The 

first  of  its  compounds  to  be  introduced  was  Phenacetine  (C6H4<QC  H         3j 

which  differs  from  antifebrine  only  in  the  addition  of  ethoxyl  in  the  para  posi- 
tion. Methacetine,  which  resembles  phenacetine  in  all  points  save  in  methoxyl 
being  substituted  for  ethoxyl,  appeared  about  the  same  time.  Phenacetine  was 
found  to  be  much  less  dangerous  than  acetanilide  and  antipyrine,  and  has  there- 
fore been  largely  used,  and  has  been  followed  by  other  bodies  which  are  identical 
with  it,  except  in  the  acid  radicle  attached  to  the  nitrogen.  Among  these 
phenetidines  may  be  mentioned  Lactophenine  (lactyl-phenetidine),  Malakine 
(salicyl-phenetidine)  and  Saliphen  and  Salophen,  which  contain  similar  constitu- 
ents, Apolysine  and  Citrophen  (citryl-phenetidine),  Kryofine  (methylglycollic- 
phenetidine)  and  Phenocoll  (glycocoll-phenetidine),  with  its  compound  with 
salicylic  acid,  Salocoll. 

Several  urethane  derivatives  have  also  received  a  trial  as  antipyretics,  among 
them  being  Euphorine  (phenylurethane),  which  is  somewhat  poisonous,  how- 
ever, Thermodine  (phenacetine-urethane)  and  Neurodine  (acetoxyphenyl-ure- 
thane). 

With  the  exception  of  antipyrine  and  the  quinoline  compounds,  all 
the  antipyretics  at  present  in  use  probably  owe  their  activity  to  the 
formation  of  simple  derivatives  of  paramidophenol  in  the  tissues, 
and  differ  chiefly  in  the  rapidity  with  which  this  decomposition  occurs. 
A  rapid  formation  of  paramidophenol  produces  destructive  blood 
changes  and  a  tendency  to  collapse,  while  the  antipyretic  effects  pass 
off  very  rapidly.  Those  drugs  are  found  the  most  satisfactory  anti- 
pyretics in  which  the  decomposition  proceeds  gradually  so  that  the 
temperature  falls  slowly  and  remains  low  for  a  longer  time.  The  sim- 
pler antipyretics,  such  as  antifebrine,  have  given  way  largely  therefore 
to  the  phenetidiue  compounds.1  Among  these  it  is  impossible  to  deter- 
mine the  most  suitable  antipyretic.  The  question  is  a  purely  clinical 
one,  and  these  drugs  are  thrown  on  the  market  in  such  profusion  at 
the  present  time  that  clinical  observers  are  unable  to  compare  their 
effects  satisfactorily,  and  in  many  cases  seem  satisfied  to  use  one  ex- 
clusively. Where  the  merits  seem  so  equally  divided,  it  is  perhaps  more 
important  to  learn  to  use  one  of  them  with  judgment  than  to  hurry 
after  each  new  product  without  sufficient  experience  of  its  predecessor. 

Symptoms.  —  The  most  interesting  effect  of  these  drugs  is  the  de- 
pression of  the  body  temperature  in  fever,  and  in  many  other  respects 
their  action  is  not  very  definitely  known  at  present.  They  are  by  no 
means  very  poisonous,  normal  animals  showing  no  reaction  to  doses 
which  are  sufficient  to  cause  marked  changes  in  fever.  In  the  frog, 
Antipyrine  causes  an  increase  in  the  reflex  irritability,  which  sometimes 

1  For  a  detailed  discussion  of  these  principles  see  V.  Mering,  Therap.  Monatsh. 
1893,  p.  577,  and  Hinsbery  &  Treupel,  Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiii.?  p.  216. 


ACETANILIDE  AND  ANTIPYRINE  SERIES.  371 

leads  to  tetanic  convulsions  and  is  followed  by  depression,  loss  of  the 
voluntary  movements,  and  eventually  by  complete  paralysis  and  death. 
In  mammals,  its  injection  is  followed  at  first  by  a  period  of  quiet  and 
sometimes  of  somnolence,  which  is  said  by  some  authors  to  occur  also 
in  the  frog  previous  to  the  increase  in  the  reflex  irritability.  Some 
rise  in  the  reflex  irritability  may  be  made  out  in  the  mammal  at  this 
stage,  and  large  doses  cause  convulsions  and  tremors,  and  subsequently 
unconsciousness  and  collapse,  ending  in  complete  paralysis.  The  pulse 
is  accelerated  by  small  doses,  while  in  the  later  stages  of  poisoning  it 
may  be  slow,  and  some  dilatation  of  the  skin  vessels  and  flushing  have 
been  observed.  The  respiration  is  at  first  accelerated,  and  then  be- 
comes slow  and  irregular  when  large  doses  are  injected.  In  dogs, 
vomiting  and  dilatation  of  the  pupil  generally  occur. 

Antifebrine  is  more  poisonous  than  antipyrine  in  both  frogs  and 
mammals,  but  resembles  it  in  its  general  effects,  producing  first  a  more 
or  less  marked  stage  of  lessened  activity,  followed  by  convulsive  move- 
ments. The  respiration  is  not  so  much  accelerated  as  by  antipyrine, 
and,  according  to  some  observers,  is  slow  from  the  beginning  of  the  ac- 
tion. The  heart  is  first  accelerated  and  then  slow  and  irregular,  and 
cyanosis  and  collapse  are  more  frequently  observed  than  under  anti- 
pyrine. Phenacetine  and  its  allies  are  much  less  poisonous  than  the 
two  foregoing,  but  in  large  quantities  produce  almost  identical  effects  — 
somnolence  followed  by  convulsions,  cyanosis  and  collapse  symptoms, 
first  rapid,  then  slow  respiration  and  heart.  Analgen,  which  may  be 
taken  as  a  type  of  the  quinoline  derivatives,  acts  in  a  very  similar  way 
to  the  others,  and  is  more  toxic  than  phenacetine,  and,  according  to 
some  writers,. than  antipyrine.  Some  depression  of  the  spontaneous 
movements  and  of  the  reflexes  is  described  as  following  its  adminis- 
tration to  mammals,  and  large  doses  produce  convulsions  and  cyanosis. 
Lactophenine  is  said  to  have  a  more  sedative  effect  than  the  other  an- 
tipyretics, and  to  induce  complete  narcosis  in  the  rabbit. 

The  Effects  of  the  antipyretics  in  Man  vary  exceedingly,  not  only 
with  the  dose  but  with  the  individual  patient.  Many  persons  can  take 
very  large  doses  without  apparent  effect,  while  in  others  comparatively 
minute  quantities  produce  symptoms  of  greater  or  less  importance.  The 
effects  are  not  always  the  same  even  in  one  individual  under  the 
same  dose  of  the  antipyretic,  and  it  is  impossible  to  state  at  present 
what  are  the  conditions  that  involve  the  peculiar  train  of  symptoms. 
A  very  large  number  of  disorders  have  been  attributed  to  the  anti- 
pyretics in  man,  but  it  is  impossible  to  consider  any  here  except  those 
more  commonly  observed.  Among  these  are  skin  eruptions  of  various 
forms,  such  as  red,  erythematous,  itching  patches  or  more  widely  dif- 
fused hyperaBmia  resembling  the  onset  of  measles  or  scarlatina ;  urti- 
caria occurs  not  uncommonly,  while  eczema  and  bullse  are  rarer.  In 
some  cases  an  cedematous  swelling  has  been  observed.  Some  fever 
occasionally  accompanies  the  eruption  and  renders  the  diagnosis  from 
the  infectious  exanthemata  even  more  difficult.  These  skin  affections 


372  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

seem  to  be  elicited  more  frequently  by  antipyrine  than  by  antifebrine 
and  the  phenetidine  compounds.  They  have  been  attributed  to  dilata- 
tion of  the  cutaneous  vessels,  but  this  in  itself  is  insufficient  to  explain 
their  appearance,  although  it  may  be  a  favoring  condition.  Profuse 
perspiration  not  infrequently  follows  the  use  of  the  antipyretics  in 
fever,  and  if  the  fall  in  temperature  be  rapid,  and  the  action  of  the 
drug  passes  off  soon,  the  subsequent  rise  of  temperature  may  be  accom- 
panied by  shivering  and  rigor,  but  these  symptoms  are  scarcely  to  be 
looked  upon  as  direct  effects  of  the  drug,  but  rather  as  resulting  from 
the  rapid  changes  in  temperature.  They  are  produced  much  more 
frequently  by  the  older  and  simpler  antipyretics  than  by  those  of  more 
recent  introduction. 

Sometimes  catarrh,  burning  and  swelling  of  the  throat  and  mouth  are 
observed  after  antipyrine,  and  more  rarely  nausea  and  vomiting.  Cerebral 
symptoms  are  rarely  elicited  beyond  slight  dulness,  confusion  or  apathy. 
Alterations  of  the  hearing  similar  to  those  described  under  quinine 
have  been  observed  in  some  cases.  More  serious  symptoms  are  those 
of  collapse,  which  are  occasionally  produced  in  susceptible  persons, 
especially  by  large  doses.  Antifebrine  is  much  more  liable  to  elicit 
these  than  antipyrine,  which  in  turn  is  more  dangerous  than  phenacetine 
and  the  other  phenetidine  derivatives.  In  the  milder  cases  of  collapse 
the  skin  is  cool,  the  pulse  is  rather  small  and  rapid,  and  some  anxiety 
and  alarm  is  felt  by  the  patient,  but  the  condition  passes  off  in  a  short 
time.  In  more  severe  cases  the  skin  is  cold  and  covered  by  a  clammy 
perspiration,  the  heart  is  weak,  irregular  and  sometimes  fluttering,  the 
temperature  may  be  subnormal  and  the  pupils  are  slightly  dilated. 
The  patient  may  be  conscious,  fainting  may  occur,  or  an  apathetic, 
confused  condition  may  be  produced.  The  weakness  of  the  heart  is 
the  chief  source  of  anxiety,  and  the  total  failure  of  the  circulation  seems 
to  be  the  cause  of  death.  These  cases  of  collapse  occur  more  frequently 
when  a  rapid  fall  of  temperature  has  been  produced  than  under  other 
circumstances,  but  may  be  observed  in  cases  in  which  no  fever  has 
been  present. 

Marked  cyanosis  occurs  occasionally  under  all  the  antipyretics,  but 
more  frequently  under  antifebrine  and  the  earlier  members  of  the  series 
than  under  antipyrine  and  the  phenetidine  compounds.  Its  chief 
cause  appears  to  be  the  formation  of  methsemoglobin  in  the  blood, 
although  it  is  said  to  have  been  present  in  some  cases  in  which  this 
pigment  could  not  be  recognized,  and  it  is  often  more  intense  than  that 
observed  from  the  action  of  other  poisons  which  lead  to  the  formation 
of  methsemoglobin.  It  is  often  accompanied  by  dyspnoea  and  accel- 
eration of  the  pulse,  and  it  lasts  for  a  varying  length  of  time,  some- 
times passing  off  in  a  few  hours,  at  other  times  persisting  for  several 
days. 

Occasionally  a  certain  tolerance  is  gained,  and  larger  doses  of  the 
antipyretics  are  required  to  produce  effect  than  were  necessary  at  the 
beginning  of  the  treatment.  A  few  cases  of  chronic  poisoning  are 


ACETANILIDE  AND  ANTIPYRINE  SERIES.  373 

recorded  from  the  habitual  use  of  these  drugs  in  neuralgia.  The 
symptoms  consisted  in  disturbance  of  the  digestion,  cyanosis,  tremor, 
excitability  and  irritability,  and  disappeared  when  the  drug  was 
given  up. 

Action.  —  The  action  of  these  drugs  on  the  various  organs  is  very 
imperfectly  understood.  They  are  generally  supposed  to  have  some 
depressant  effect  on  the  Nerve  Centres,  as  is  shown  by  the  lessened 
movements  and  slight  somnolence  produced  in  man  and  animals.  This 
effect  is  very  slight  in  many  cases,  however,  and  it  seems  impossible 
to  suppose  that  the  action  is  in  any  way  comparable  to  that  of  the  true 
narcotics,  for  cerebral  action  may  be  induced  by  small  doses  which  do 
not  apparently  influence  the  mental  activity.  Thus,  neuralgic  pain  is 
often  relieved  by  the  antipyretics  without  causing  somnolence  or  any 
appreciable  depression,  and  it  would  therefore  appear  that  if  the  ordi- 
nary doses  influence  the  activity  of  the  nerve  cells,  they  must  do  so 
to  a  very  slight  extent,  or  perhaps  their  action  may  be  confined  to  some 
special  areas  of  the  brain.  Most  of  the  antipyretics  increase  the  ex- 
citability of  the  spinal  cord  at  first,  and  this  may  lead  to  convulsions 
in  the  frog.  The  origin  of  the  convulsions  in  mammals  is  still  some- 
what doubtful ;  in  general,  they  seem  to  be  of  cerebral  origin,  but 
when  large  quantities  are  injected,  they  are  seen  even  when  the  spinal 
cord  is  divided  from  the  brain,  so  that  the  cord  appears  to  be  thrown 
into  a  condition  resembling  that  discussed  under  strychnine  poisoning. 
In  considering  the  cause  of  these  convulsions  perhaps  too  little  weight 
has  been  laid  by  some  writers  on  the  changes  in  the  blood,  respiration 
and  circulation,  for  it  is  possible  that  the  convulsions  in  some  cases  are 
asphyxial  in  character,  and  not  due  to  the  direct  action  of  the  poisons 
on  the  brain.  In  ordinary  poisoning  the  peripheral  Nerves  and  nerve 
ends  do  not  seem  to  be  seriously  involved  and  the  final  paralysis  in 
both  frogs  and  animals  is  undoubtedly  central.  Santessou  found 
that  antipyrine  tended  to  increase  the  power  of  the  frog's  Muscles,  and 
several  observers  have  noted  that  the  nerves  and  motor  terminations 
are  paralyzed  by  the  direct  application  of  this  drug.  Antipyrine  has 
some  effect  as  a  local  anesthetic  when  applied  to  the  mucous  membranes. 

The  Heart  in  the  frog  and  mammals  is  first  accelerated  and  then 
slowed  by  the  antipyretics  in  general,  these  alterations  being  entirely 
independent  of  the  inhibitory  mechanism  and  due  to  a  direct  effect  on 
the  cardiac  muscle.  The  increased  rhythm  of  the  heart  leads  to  a 
slight  rise  in  the  blood-pressure,  which  sinks  again  as  the  pulse  becomes 
slower.  There  is  no  satisfactory  proof  that  the  vaso-motor  centres  are 
involved  in  the  rise  of  pressure,  although  it  is  not  unlikely  that 
they  undergo  a  primary  stimulation  at  the  same  time  as  the  respiratory 
centre.  The  vessels  are  said  to  be  dilated  by  the  perfusion  of  antipy-^ 
rine  solutions,  but  it  seems  improbable  that  this  plays  any  role  in  or-, 
dinary  methods  of  application. 

Most  of  this  series  except  antipyrine  and  its  compounds  tend  to 
cause  alterations  in  the  Red  Blood  Cells  when  they  are  given  in  large 


374  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

quantities.  This  action  is  manifested  especially  by  the  simpler  bodies 
of  the  series,  and  is  still  more  marked  in  poisoning  from  aniline, 
phenylhydrazine,  paramidophenol  or  quinoline.  On  the  other  hand, 
most  of  the  phenetidine  compounds  produce  it  much  more  rarely,  and 
antipyrine  seems  devoid  of  this  action.  The  alteration  consists  in  the 
formation  of  methsemoglobin,  which  may  be  readily  detected  by  its 
characteristic  spectroscopic  appearance.  Small  quantities  of  the  anti- 
pyretics cause  its  formation  within  the  blood-cells,  which  remain  intact, 
but  larger  doses,  especially  of  the  more  poisonous  members,  destroy  the 
red  blood  cells  and  free  the  metha3moglobin  in  the  plasma.  In  the 
blood  various  distorted,  shrunken  red  cells  may  be  observed,  often  en- 
tirely devoid  of  coloring  matter,  while  part  of  the  methsemoglobin  seems 
to  escape  through  the  kidneys,  and  nephritis  occurs  in  some  cases  with 
albumin,  hemoglobin  and  even  blood  in  the  urine.  This  effect  on  the 
blood  seems  due  to  the  decomposition  of  the  antipyretics  and  the  flood- 
ing of  the  tissues  with  paramidophenol,  or  the  corresponding  quinoline 
derivative.  This  decomposition  proceeds  more  slowly  in  phenacetine 
and  its  allies  and  is  absent  after  antipyrine,  which  explains  the  rarity  of 
the  symptoms  after  these  drugs.  When  the  antipyretics  are  added  to 
blood  outside  the  body  no  methaBmoglobin  is  formed.  Whether  the 
simpler  bodies,  such  as  paramidophenol,  are  equally  inert  in  the  test- 
tube  is  unknown. 

All  of  the  antipyretics  have  some  Antiseptic  action,  which  varies  in 
the  different  members  with  their  solubility  and  stability.  Antipyrine 
is  found  to  preserve  blood  from  putrefaction  for  some  days  when  added 
to  it  so  as  to  form  a  solution  of  2-5  per  cent.  Watery  solutions 
of  this  strength  destroy  protozoa  and  stop  the  movements  of  the 
leucocytes,  but  antipyretics  administered  to  the  higher  animals  have 
no  such  effect  on  the  emigration  of  the  leucocytes  from  the  vessels  as  is 
seen  under  quinine. 

The  action  of  the  antipyretics  on  the  Metabolism  of  healthy  men 
and  animals  has  been  the  subject  of  a  number  of  investigations  which 
have  given  by  no  means  uniform  results,  especially  in  regard  to  the 
nitrogen  elimination.  Antipyrine  has  no  influence,  or  only  an  insignif- 
icant one,  on  the  metabolism  of  the  healthy  tissues,  whether  this  be 
measured  by  the  nitrogenous  excretion  or  by  the  gaseous  exchange  in 
the  lungs. 

Antifebrine,  on  the  other  hand,  has  a  distinct  effect  on  the  nitrogen 
eliminated,  although  this  is  only  elicited  by  large  doses.  After  ordi- 
nary quantities  the  urea  and  total  nitrogen  of  the  urine  may  be 
slightly  augmented,  but  in  large  doses  antifebrine  causes  an  increase 
of  30—35  per  cent,  in  ti^ese,  which  indicates  a  large  increase  in  the 
tissue  waste.  The  other  antipyretics  have  not  been  examined  so  care- 
fully. Thalline  is  said  by  Kumagawa  to  increase  the  nitrogen  elimi- 
nated like  antifebrine,  while  some  others  have  been  said  to  lessen  the 
metabolism  in  health,  but  these  statements  require  confirmation.  As 
regards  the  oxidation  in  the  tissues  as  measured  by  the  exchange  of 


ACETANILIDE  AND  ANTtPYRlNE  SERIES.  375 

gases  in  the  lungs,  the  antipyretics  have  not  been  shown  to  have  any 
effect  in  healthy  animals. 

The  excretion  of  uric  acid  under  the  antipyretics  has  also  been  the 
subject  of  repeated  examination,  but  no  definite  change  has  been  found 
to  be  induced  by  them.  The  glycogen  of  the  liver  and  muscle  is 
increased  by  antipyrine  according  to  a  recent  statement  of  Lepine  and 
Porteret,  and  Iwanoif  has  described  some  obscure  changes  in  the  liver 
cells  of  the  frog  under  antipyrine. 

The  specific  effects  of  the  antipyretics  on  the  Temperature,  while  rec- 
^bgnized  by  all,  have  been  the  subject  of  endless  discussion,  owing  to 
the  complex  mechanism  through  which  they  are  elicited.  In  the  nor- 
mal animal  the  temperature  is  but  little  altered,  except  by  doses  large 
enough  to  produce  collapse,  but  when  it  is  abnormally  high,  as  in  fever, 
the  antipyretics  cause  a  fall  of  greater  or  less  extent.  This  fall  in  tem- 
perature occurs  at  varying  intervals  after  the  ingestion  of  the  drug,  but, 
except  in  refractory  cases,  always  begins  within  2-3  hours.  Its  extent 
varies,  the  temperature  sometimes  reaching  the  normal  or  even  a  sub- 
normal point,  while  in  others  the  change  is  insignificant.  Continuous 
fever  without  any  natural  rise  and  fall  is  much  less  affected,  as  a 
general  rule,  than  one  with  alternate  rise  and  fall  of  the  temperature, 
and  in  the  latter  form  the  result  is  much  greater  if  the  drug  be  given 
at  the  beginning  of  one  of  the  natural  remissions. 

The  fall  in  temperature  is  often  accompanied  by  flushing  of  the  skin 
and  perspiration.  The  oxygen  absorbed  and  the  carbonic  acid  excreted 
are  lessened,  and  the  urea  and  nitrogen  of  the  urine  are  also  dimin- 
ished after  antipyrine,  while  they  are  not  infrequently  increased  after 
antifebrine,  especially  when  administered  in  large  quantities.  The 
heart  is  often  reduced  in  rate,  and  the  pulse  improves  in  strength,  but 
these  changes  are  due  to  the  fall  in  the  temperature  and  not  to  the 
direct  action  of  the  drugs.  Some  remedies  owe  their  antipyretic  prop- 
erties to  their  increasing  the  secretion  of  the  sweat  glands,  but  although 
perspiration  not  infrequently  occurs  during  the  fall  of  temperature  under 
the  new  antipyretics,  this  is  merely  a  secondary  result  here,  for  when 
the  perspiration  is  checked  by  atropine  or  agaricin,  the  fall  of  tempera- 
ture proceeds  uninterruptedly. 

The  temperature  in  healthy  warm-blooded  animals  is  kept  uniform 
through  a  balance  being  established  between  the  heat  formation  and  its 
dissipation  through  the  lungs,  skin  and  other  organs.  If  an  excessive 
formation  occurs,  as  during  muscular  exertion,  this  is  counterbalanced 
by  an  increase  in  the  output  from  the  skin  through  the  dilation  of  the 
vessels  and  by  the  perspiration.  If,  on  the  other  hand,  more  heat  is 
dissipated  than  usual  through  exposure  to  coldpthe  combustion  of  the 
tissues  is  increased  and  more  heat  is  formed.  The  output  of  heat  is 
thus  determined  by  the  degree  of  dilatation  of  the  cutaneous  vessels  and 
the  activity  of  the  sweat  glands,  while  the  amount  of  heat  formed  varies 
with  the  voluntary  and  involuntary  contractions  of  the  muscles.  In 
order  to  preserve  a  balance  between  these  two  factors,  there  must  exist 


376  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

a  coordinating  mechanism,  and  this  is  supposed  to  be  located  in  the 
basal  ganglia  of  the  cerebrum,  in  the  region  of  the  corpus  striatuin. 
Lesions  in  this  neighborhood  generally  cause  a  very  marked  rise  in  the 
temperature,  often  without  further  disturbance,  and  it  is  of  interest  to 
learn  that  as  long  as  the  cerebrum  is  intact,  shivering  is  produced  by 
cold,  while  after  the  section  of  the  peduncles  the  animal  offers  no 
•resistance  to  a  fall  of  temperature  produced  by  cooling  of  the  surface. 

Other  facts  might  also  be  adduced  to  show  that  in  the  normal  ani- 
mal the  temperature  is  kept  uniform  by  this  coordinating  mechanism, 
which  controls  both  the  output  of  heat  through  the  skin  and  its  for- 
mation by  the  contractions  of  the  skeletal  muscles.  In  many  indi- 
viduals this  coordination  is  not  perfect  in  health,  and  in  all  it  may  be 
disorganized  by  poisons,  such  as  those  formed  in  fever.  The  more 
perfect  the  coordination,  the  smaller  is  the  divergence  from  the  normal 
temperature  necessary  to  elicit  a  protective  increase  in  the  combustion 
or  in  the  dissipation.  The  efficiency  of  the  mechanism  may  therefore 
be  measured  by  observing  what  fall  of  the  body  temperature  occurs 
before  shivering  sets  in,  what  rise  produces  dilation  of  the  cutaneous 
vessels  and  perspiration.  In  this  way  it  has  been  found  that  during 
fever  the  coordination  is  quite  as  perfect  as  in  health,  but  that  the  pro- 
tective reactions  are  induced  at  a  higher  temperature.  Thus,  Richter 
found  that  a  normal  dog  (temperature  38.6°  C.)  protected  itself  by 
shivering  when  its  temperature  was  reduced  by  cold  to  37.9°,  while 
profuse  perspiration  broke  out.  when  its  temperature  was  raised  to 
39.1°.  The  same  dog  suffering  from  'fever  (temperature  40.4°  C.) 
reacted  by  shivering  when  its  temperature  was  reduced  to  40.2°  and 
by  perspiration  when  it  rose  to  40.9°.  The  coordination  is  not  de- 
stroyed or  paralyzed  by  fever  therefore,  for  it  is  in  this  case  more 
sensitive  to  alterations  of  the  body  temperature  than  in  the  normal 
animal.  The  same  measures  are  taken  to  preserve  a  uniform  temper- 
ature as  in  health,  but  the  temperature  maintained  by  these  means  is 
higher.  If  a  comparison  be  made  with  the  thermostat  of  the  labora- 
tory, it  may  be  said  that  in  fever  the  mechanism  is  "  set "  for  a  higher 
temperature  than  in  normal  life,  but  that  the  apparatus  acts  efficiently 
for  each  temperature.  This  higher  temperature  is  maintained  by  an 
increased  metabolism  or  heat  formation,  and  also  in  most  cases  by  a 
lessened  dissipation.  The  fever  temperature  itself  seems  to  increase 
the  metabolism,  the  tissues  undergoing  more  rapid  waste  under  it  than 
in  normal  conditions.1 

The  first  explanation  of  the  antipyretic  action  of  this  series  was* 
that  they  lessened  the  metabolism  in  the  same  way  as  quinine,  and 
thus  lessened  the  heat  production.  This  view  was  suggested  by  the 
fact  that  some  of  them,  such  as  kairine  and  thalline,  are  derivatives  of 
quinoline,  like  quinine,  and  it  was  supported  by  the  observation  that  the 

1  It  must  not  be  supposed  from  the  foregoing  statements  that  fever  consists  only  in 
an  alteration  of  the  normal  temperature.  This  is  only  one  of  the  symptoms  produced 
by  the  poisons  of  fever,  but  is  the  only  one  affected  by  the  antipyretics. 


ACETANILIDE  AND  ANTIPYRINE  SERIES. 


377 


nitrogen  eliminated  and  the  oxygen  absorbed  were  reduced  in  amount 
by  their  action  in  fever,  and  by  a  series  of  calori metric  experiments  in 
which  it  appeared  that  the  output  of  heat  was  lessened  by  their  use. 
This  explanation  has  of  late  years  been  abandoned  by  the  great  ma- 
jority of  the  investigators  of  the  subject.  The  lessened  tissue  waste 
which  is  observed  under  the  action  of  the  antipyretics  in  fever  is  not 
due  to  their  direct  action  on  the  tissues,  but  to  the  fall  of  temperature, 
the  metabolism  proceeding  more  slowly  when  the  heat  is  reduced. 
If  they  acted  on  the  tissues  directly  in  fever,  they  would  have  a  similar 
effect  in  health  (cf.  quinine),  whereas  antipyrine  has  no  appreciable 
effect  here,  and  antifebrine  actually  increases  tissue  waste. 

The  earlier  experiments  in  which  the  dissipation  of  heat  was 
measured  directly  by  the  calorimeter  indicated  that  it  was  lessened 
by  the  antipyretics,  in  fever, 

while   the   results  varied    in  FIG.  35. 

health.  Renewed  investi- 
gations with  more  atten- 
tion to  detail  and  with  im- 
proved apparatus  have  shown, 
however,  that  the  dissipation 
of  heat  in  fever  is  much  in- 
creased by  the  antipyretics, 
while  in  health  they  seem  to 
have  little  effect.  This  aug- 
mentation in  the  output  is 
due  to  dilatation  of  the  cu- 
taneous vessels,  which  exposes 
a  large  amount  of  blood  to 
the  cold  air.  The  dilatation 
is  great  enough  to  be  recorded 
by  the  plethysmograph  in 
many  cases,  while  in  others 
flushing  of  the  skin  may  be  A  H  P  B 

Observed.  The  increased  dis-  Diagram  to  mustrate  the  relation  between  the  warmth 

sipation  of  heat  is  aCCOm-  output  and  the  internal  temperature.  The  unbroken 

"  .  _.  .  .  .  line  represents  the  changes  in  the  warmth  output,which 

pamed  by  a  lessened  formation  is  estimated  at  different  times  by  measuring  the  height 

i.  i  i  .  ,  T  of  this  line  from  the  abscissa  A  B.  The  broken  line  is 
Which,  however,  IS  much  leSS  that  of  the  internal  temperature.  A  to  H  normal  ;  at  If 
4.  J  U*  U  '  an  injury  of  the  brain  caused  a  marked  fall  in  the  out- 
important  and  Which  IS  gener-  put  and  an  increase  in  the  internal  temperature,  which 


ally  attributed  to  the  metab- 

olism  proceeding  less  actively    ™£JX£v.'S£H2;*(?>lltr"t  F'g' 33' 
at  the  lower  temperature.    In 

other  words,  the  antipyretics  reduce  the  tenaperature  by  increasing 
the  output  of  heat,  and  the  cells  of  the  body  grow  and  change 
less  when  removed  from  the  hot-house  temperature  to  which  they 
have  been  exposed  previously.  It  must  be  added,  however,  that 
sonic  observers  hold  that  the  fall  in  heat  formation  is  too  great  to  be 
explained  in  this  way,  and  suppose  that  the  antipyretics  lessen  the 


378  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

combustion  through  some  other  action,  but  not  by  affecting  the  tis- 
sues directly. 

It  has  been  stated  already  that  the  fevered  animal  resists  any  change 
in  its  temperature  in  the  same  way  as  the  normal,  and  it  might  there- 
fore be  expected  that  when  the  temperature  is  reduced  by  antipyretics 
the  organism  would  at  once  increase  its  heat  formation.  The  fact  that 
this  does  not  occur,  but  that,  on  the  contrary,  the  metabolism  is  les- 
sened, indicates  that  some  further  change  occurs,  that  the  antipyretics 
not  only  reduce  the  temperature  by  allowing  the  heat  to  escape,  but 
also  alter  the  condition  of  the  coordinating  mechanism  by  which  the 
temperature  is  kept  uniform.  To  return  to  the  comparison  with  a 
thermostat,  the  body  temperature  is  set  at  a  lower  point  by  the  anti- 
pyretics, while  it  is  set  higher  by  the  fever  poisons. 

The  action  of  the  antipyretics  on  this  coordinating  centre  is  there- 
fore of  interest,  and  has  been  examined  both  in  health  and  disease. 
In  healthy  men  the  temperature  does  not  undergo  any  marked  change 
under  the  antipyretics  for  though  it  may  fall  a  few  tenths  of  a  degree 
in  some  cases,  this  is  of  no  significance.  The  sensitiveness  of  the  coordi- 
nating centre  is  increased  apparently,  however,  for  in  some  individuals 
in  whom  hard  muscular  work  causes  a  rise  of  temperature  normally, 
this  is  absent  or  less  marked  after  the  antipyretics.  In  the  same  way 
the  rise  of  temperature  which  occasionally  is  caused  by  very  hot  baths, 
is  absent  or  diminished  when  antipyrine  has  been  administered  pre- 
viously. When  the  basal  ganglia  are  cut  off  from  their  connections 
with  the  lower  part  of  the  body,  neither  septic  injections  nor  antipy- 
retics have  any  effect  on  the  temperature,  while  after  section  above 
the  basal  ganglia,  fever  is  caused,  and  the  antipyretics  induce  the 
usual  fall  of  temperature  (Sawadowsky).  In  experiments  in  which  a 
high  fever  was  produced  by  lesions  in  the  neighborhood  of  the  ganglia, 
Gottlieb  found  that  the  antipyretics  reduced  the  temperature  and  in- 
creased the  output  of  heat  to  a  marked  extent,  while  the  formation  was 
increased  to  a  less  degree. 

Finally,  the  condition  of  the  centre  has  been  examined  by  Stern  and 
Kichter  after  the  temperature  had  been  reduced  by  antipyretics. 
They  both  found  that  the  protective  mechanism  was  called  into  play 
when  the  temperature  was  slightly  raised,  and  generally  when  it  was 
depressed.  For  example,  a  fevered  dog  (temperature  40.9°  C.)  re- 
ceived a  dose  of  kairine,  and  its  temperature  was  reduced  to  37.6.° 
Attempts  were  now  made  to  raise  the  temperature  by  external  heat,  but 
the  animal  resisted  this  by  increasing  the  output  as  soon  as  the  tem- 
perature rose  to  37.8°.  The  coordination  which  maintained  the  tem- 
perature at  40.9°  before  the  drug  was  administered  now  attempted  to 
keep  it  at  37.6°. 

The  results  of  these  researches  may  be  summed  up  shortly  as  fol- 
|  lows  :  The  antipyretics  reduce  the  temperature  in  fever  through  alter- 
ations effected  in  the  heat-regulating  nervous  mechanism,  wHich  result  in 
lowering  the  point  at  which  the  temperature  is  maintained.  As  a  couse- 

,-..rw,»*.**'W'«***1     :"'   ''^-^^"'  •"•*•    ""--'-* 


ACETANILIDE  AND  ANTIPYRINE  SERIES. 


379 


38 
37 
36 
35 
34 
33 


31 


P    I 


quence  of  this  action,  a  great  increase  in  the  dissipation  of  heat  must 
occur  in  order  to  free  the  body  from,  the  warmth  which  it  has  accumu- 
lated, and  this  increased  output 

is   attained  by  dilatation  of  the  FIG.  36. 

cutaneous  vessels.  The  seat  of 
action  of  the  antipyretics  is 
probably  situated  in  the  base.,of 
the  cerebrum. 

The  precise  nature  of  the 
changes  wrought  by  the  antipy- 
retics in  the  coordinating  mech- 
anism is  unknown.  Gottlieb 
and  Harnack  suggest  that  it  is 
depressed  by  them  and  this 
would  accord  with  the  widely 
held  idea  that  fever  temperature 
is  due  to  some  form  of  brain  ir- 
ritation ;  but  their  reasoning  is 
open  to  objection,  and  specula- 
tion seems  useless  until  more  30 
is  learned  regarding;  the  normal 

.                   &  Curve    of   the  internal  temperature    (unbroken 

function  Ot  thlS  Organ.  line)  and  of  the  skin  temperature  (dotted  line)  in 

^TT,            ,,                                         .  ,          fever  treated  with  antipyrine  (Roseuthal).     The  ab- 

When    the    temperature  IS  de-     scissa  AS  represents  the  time  in  hours,  the  vertical, 

pressed    too    rapidly    by    these    ^  S!£Tffffto  ®S^^^E^ 

remedies,  a  condition  of  collapse 

is  often  produced,  while  in  other 

cases  the  loss  of  heat  caused  by 

the  dilatation  of  the  skin  vessels  seems  to  be  excessive,  and  shivering 

and  rigor  follow  in  order  to  increase  the  production. 

When  the  temperature  has  reached  the  new  point  fixed  by  the  coor- 
dination under  the  influence  of  the  antipyretic,  the  heat  dissipation 
rapidly  diminishes  and  may  become  less  than  normal,  because  the  new 
temperature  is  maintained  at  a  constant  point  by  the  same  mechanism 
as  the  normal. 

The  antipyretics  are  rapidly  absorbed,  and  as  rapidly  Excreted  by 
the  kidneys,  so  that  they  disappear  from  the  body  within  24-30  hours 
after  their  administration. 

The  fate  of  antipyrine  seems  to  differ  in  different  animals.  In  the  dog  it 
is  found  to  be  partially  oxidized  to  oxyantipyrine  which  is  excreted  in  the 
urine  in  combination  with  glycuronic  and  sulphuric  acids.  In  others  it  is 
said  to  be  excreted  in  the  urine  unchanged.  Antifebrine  undergoes  a  partial 
oxidation,  the  final  product  differing  in  different  animals,  but  none  of  the 
original  body  appears  in  the  urine  except  after  very  large  doses.  In  man  it 

appears  as  acetylparamidophenol  (C6H4  <OTT   2    3    )  and  as  paramidophenol 

or  another  of  its  compounds,  both  being  in  combination  with  sulphuric  and 
glycuronic  acids.  In  the  rabbit's  urine  paramidophenol  alone  is  found,  while 

in  the  dog  this  is  accompanied  by  oxycarbanil  (C6H4  <  >  CO) ;  in  each 
case  it  forms  a  double  sulphate  or  glycuronate.  The  fate  of  the  other  anti- 


temperature fel1  again  as the 


380  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

pyretics  resembles  that  of  antifebrine,  the  quinoline  derivatives  undergoing  a 
partial  oxidation  resulting  in  a  body  analogous  to  paramidophenol,  while  the 
phenetidine  compounds  are  partially  decomposed  and  appear  in  the  urine  as 
glycuronates  of  pheuetidine.  The  combinations  containing  salicylic  acid 
break  up  in  the  body,  and  the  acid  appears  in  the  urine  as  salicyluric  acid, 
while  the  rest  of  the  molecule  undergoes  the  usual  partial  oxidation. 

The  presence  in  the  urine  of  these  bodies,  or  rather  of  further  pro- 
ducts of  their  oxidation,  gives  it  a  dark  reddish-brown  color,  which  may 
be  observed  when  it  is  passed,  or  more  frequently  after  it  has  been  ex- 
posed to  the  air  for  some  time. 

PREPARATIONS. 

ACETANILTDUM  (U.  S.  P.,  B.  P.),  acetanilide  or  antifebrine. 

Acetanilide  is  a  colorless,  crystalline  body  insoluble  in  water,  soluble  in 
alcohol,  ether  and  chloroform.  It  has  no  odor  when  pure,  but  has  a  slight 
burning  taste.  It  may  be  prescribed  in  powder,  suspended  in  mucilage,  or 
in  cachets  or  lozenges.  The  B.  P.  gives  as  the  dose  0.06-0.2  G.  (1-3  grs.),  but 
it  is  often  given  in  larger  doses,  up  to  0.6  G.  (10  grs.). 

Pulvis  Acetanilidi  Compositus  (U.  S.  P.)  contains  7  parts  of  antifebrine,  1  of 
caffeine,  and  2  of  sodium  bicarbonate.  Dose,  0.5  G.  (7£  grs.). 

ANTIPYRINA  (U.  S.  P.),  PHENAZONUM  (B.  P.)  phenazone,  or  ANTIPYRIKE, 
forms  colorless  inodorous  crystals,  with  a  bitter  taste,  very  soluble  in  water, 
alcohol  and  chloroform.  0.3-1.3  G.  (5-20  grs.). 

PHENACETINUM  (B.  P.),  ACETPHENETIDINUM  (U.  S.  P.),  colorless,  tasteless 
crystals,  insoluble  in  water,  0.3-1  G.  (5-15  grs.),  in  the  same  forms  as  acet- 
anilide. 

Non- official. 

Thalline  is  generally  seen  as  thalline  sulphate,  a  colorless  crystalline  sub- 
stance, of  a  weak  aromatic  odor  and  slightly  bitter  taste,  soluble  in  7  parts 
of  water.  0.2-0.5  G.  (3-8  grs.). 

Exalgine  resembles  acetanilide  except  in  its  greater  solubility  in  water, 
and  may  be  given  in  the  same  quantity. 

Malakine,  Lactophenine,  Thermodine,  Neurodine,  Saliphen  and  Salophen  all 
resemble  each  other  in  being  insoluble  in  water,  colorless  and  crystalline, 
and  are  prescribed  in  the  same  way  as  acetanilide  and,  in  doses  of  0. 5-1  G. 

Phenocoll  is  generally  used  as  the  hydrochlorate,  which  is  fairly  soluble  in 
water,  while  Salocoll  is  insoluble.  0.5-1  G.  (8-15  grs.). 

Malakine,  Saliphen,  Salocoll  and  Salophen  all  break  up  in  the  body,  freeing 
salicylic  acid,  so  that,  in  addition  to  the  antipyretic  action,  the  characteristic 
effects  of  this  acid  may  be  elicited  by  them. 

The  antipyretics  are  almost  invariably  given  by  the  mouth.  Antipyrine 
has  been  injected  hypodermically,  but  is  somewhat  painful,  because  much 
larger  quantities  have  to  be  used  than  are  generally  given  by  this  method, 
and  the  solutions  have,  therefore,  to  be  more  concentrated  (30-50  per  cent.). 

Therapeutic  Uses. — The  antipyretics  are  used  chiefly  to  Reduce  the 
Fever  Temperature.  The  most  satisfactory  results  are  obtained  from 
those  which  act  somewhat  slowly,  but  which  preserve  a  low  temperature 
for  some  time,  and  antipyrine  and  the  phenetidine  compounds  are  thus 
preferable  to  the  earlier  remedies,  which  produce  a  more  abrupt  fall,  after 
which  the  temperature  soon  regains  its  former  height.  The  best  effects 
are  obtained  when  the  antipyretic  is  given  at  the  commencement  of  a 
natural  remission,  the  temperature  often  falling  2—4  degrees  in  the  course 
of  the  next  2—3  hours,  and  only  rising  slowly  afterwards.  In  some 


ACETANILIDE  AND  ANTIPYEINE  SERIES.  381 

fevers  the  antipyretics  have  much  less  tendency  to  lower  the  tempera- 
ture than  in  others.  Thus  in  septicaBmia  larger  doses  are  required  than 
in  typhoid  and  not  infrequently  no  satisfactory  reduction  of  the  tempera- 
ture follows  the  administration  of  the  maximal  quantity.  Pneumonia 
is  also  said  by  some  writers  not  to  be  affected  so  easily  as  some  other 
febrile  conditions  in  which  the  heat-regulating  centre  appears  to  be  in 
a  less  stable  condition,  as  is  manifested  by  the  occurrence  of  large  spon- 
taneous variations  of  temperature.  The  reduction  of  the  temperature 
by  the  antipyretics  lasts  only  as  long  as  the  drug  is  present  in  sufficient 
quantity  in  the  body,  and  accordingly  as  soon  as  sufficient  has  been 
excreted,  the  intoxication  of  the  regulating  mechanism  begins  again,  and 
the  temperature  soon  rises  to  its  former  height.  The  antipyretics  do  not 
act  on  the  cause  of  the  disease,  but  only  remove  one  of  the  symptoms, 
but  this  in  itself  is  not  an  argument  against  their  use,  as  is  apparently 
believed  by  some  writers,  because  as  long  as  the  physician  is  unable 
to  treat  the  cause  directly,  he  is  justified  in  taking  such  measures  as 
are  possible  to  remove  the  symptoms,  rather  than  in  adopting  an  ex- 
pectant treatment,  pure  and  simple.  The  extensive  use  of  these  reme- 
dies shows  very  clearly  that  the  high  temperature  is  merely  a  symp- 
tom of  disease,  and  not  the  disease  itself,  and  the  question  has  been 
much  debated  as  to  whether  the  reduction  of  fever  is  in  any  way  bene- 
ficial. No  one  questions  that  some  antipyretic  measures  should  be 
taken  when  the  temperature  rises  so  high  as  to  form  a  danger  in  itself, 
but  their  use  in  ordinary  fever  cases  is  more  doubtful,  and  many 
physicians  deprecate  their  use  unless  in  exceptional  cases.  The 
very  large  doses  formerly  used  undoubtedly  induced  dangerous  symp- 
toms occasionally,  but  there  is  little  risk  of  this  occurring  from 
the  intelligent,  use  of  the  less  violent  members  of  the  series. 
It  has  recently  been  shown  by  Schutze  and  Beniasch  that  the  use 
of  the  antipyretics  does  not  retard  the  formation  of  the  protective 
substances  (antitoxins)  to  which  the  recovery  from  fever  is  attributed, 
for  in  infected  animals  treated  with  enormous  quantities  of  antipyrine 
the  serum  displayed  the  same  agglutinating  properties  towards  the 
bacilli  as  that  of  controls  which  were  not  subjected  to  any  medication. 
A  more  serious  argument  against  their  use  in  fever  is  that  the  course 
of  the  disease  is  less  readily  followed,  because  one  of  the  guiding  symp- 
toms—  the  temperature  variations  —  is  no  longer  dependent  solely 
upon  the  severity  of  the  intoxication  with  the  fever  poisons,  and  both 
diagnosis  and  prognosis  are  thus  rendered  more  difficult.  For  example, 
in  typhoid  fever  a  sudden  fall  of  temperature  often  gives  the  first  in- 
dication of  such  a  complication  as  hemorrhage,  but  if  an  antipyretic 
has  been  given  beforehand,  this  indication  may  be  entirely  absent.  On 
the  other  hand,  it  is  urged  in  favor  of  the  antipyretic  treatment  that 
the  patient  feels  more  comfortable  and  easier  when  the  temperature  is 
reduced,  and  that  this  alone  may  favorably  influence  the  course  of  the 
disease.  Besides,  the  high  temperature  in  itself  increases  the  tissue 
waste,  and  causes  larger  draughts  on  the  resources  of  the  patient  than 
would  be  made  with  the  same  amount  of  poison  in  the  tissues  at  a 


382  ORGANIC  DRUGS  ACTING   AFTER  ABSORPTION. 

lower  temperature  ;  and  although  the  influence  of  the  high  temperature 
on  the  metabolism  was  undoubtedly  exaggerated  at  one  time,  this  con- 
sideration is  by  no  means  devoid  of  weight.  The  theory  that  fever  is 
a  defensive  measure  taken  by  the  organism  against  the  causes  of  dis- 
ease and  ought  not  to  be  interfered  with  therefore,  is  now  seldom  men- 
tioned. The  antipyretic  treatment  of  fever  is  of  value,  then,  in  cases 
where  the  temperature  is  so  high  as  to  endanger  life,  in  cases  in  which 
the  rise  of  temperature  is  the  chief  cause  of  distress  and  no  complica- 
tions are  to  be  apprehended,  and,  in  general,  in  cases  in  which  the 
increased  comfort  of  the  patient  is  not  counterbalanced  by  their  ob- 
scuring the  diagnosis  and  prognosis.  On  the  other  hand,  there  is  no 
reason  to  suppose  that  it  lessens  the  mortality  or  shortens  the  course 
of  most  fevers,  or  that  it  prevents  complications  of  any  kind  except 
excessively  high  temperature,  and  the  routine  treatment  of  fever  with 
antipyretics  is  to  be  deprecated. 

The  chief  rival  of  the  antipyretics  in  the  treatment  of  fever  in  the 
present  day  is  the  so-called  cold-bath  treatment,  in  which  the  fever 
patient  is  bathed  frequently  in  water  the  temperature  of  which  varies 
from  70-90°  F.  in  different  hospitals.  The  temperature  generally  falls 
to  a  considerable  extent  under  this  treatment,  and  very  often  a  general 
improvement  in  the  symptoms  occurs.  The  effect  on  the  temperature 
is  mainly  due  to  the  abstraction  of  heat  from  the  body,  and  thus 
far  corresponds  to  that  of  the  antipyretics.  In  the  cold-bath  treat- 
ment, however,  the  loss  of  heat  is  not  immediately  due  to  the  dilata- 
tion of  the  skin  vessels,  for  baths  at  70°  F.  have  rather  the  effect 
of  constricting  the  vessels  primarily,  whatever  may  be  the  sub- 
sequent effect.  The  heat  output  increases  here  from  the  change  in 
the  external  medium,  and  not  from  any  alteration  in  the  skin  itself. 
The  fall  of  temperature  is  generally  not  so  great  as  under  the  anti- 
pyretics, and  the  regulation  is  not  directly  affected,  for  the  patient 
shivers  and  becomes  cyanotic  long  before  the  normal  temperature  is 
reached.  The  therapeutic  virtue  of  the  cold  bath  was  formerly  believed 
to  lie  exclusively  in  the  abstraction  of  heat  and  the  fall  of  temperature, 
but  many  advocates  of  the  treatment  now  hold  that  this  is  of  less  im- 
portance than  the  effects  on  the  circulation  and  the  brain,  which  are 
elicited  reflexly  by  the  cold  water  applied  to  the  skin,  and  which  are 
not  now  believed  to  be  due  to  the  fall  in  temperature.  Whether  this 
view  is  correct  or  not,  the  whole  nature  of  the  fall  in  temperature  is 
different  from  that  produced  by  the  antipyretics,  and  the  metabolism, 
instead  of  becoming  less  active  as  it  does  under  the  latter,  rather  tends 
to  increase  under  the  cold  baths,  at  least  as  far  as  the  tissue  change  can 
be  measured  by  the  nitrogen  excreted.  The  relative  therapeutic  value 
of  the  two  methods  of  treating  fevers  can  only  be  determined  by  clin- 
ical experiment,  and  the  present  attitude  of  the  clinicians,  which  tends 
to  favor  the  cold-bath  treatment,  may  be  reversed  in  course  of  time. 
However  the  matter  may  stand  in  hospital  practice,  in  which  trained 
assistance  is  available,  the  antipyretics  have  a  great  advantage  in  many 
cases  in  which  treatment  has  to  be  carried  out  without  any  such  faciK- 


ACETANILIDE  AND  ANTIPYRINE  SERIES.  383 

ties,  for  the  administration  of  these  drugs  may,  of  course,  be  entrusted 
to  ordinary  persons,  whereas  the  cold  bath  can  be  given  only  by 
the  physician  himself  or  by  trained  attendants.  Particularly  in  the 
milder  fevers,  where  no  complicated  measures,  such  as  the  cold  bath, 
are  considered  necessary,  the  antipyretics  give  relief  to  the  patient  by 
removing  the  feeling  of  heat  and  discomfort. 

Other  antipyretic  drugs  are  quinine,  aconite,  digitalis,  and  alcohol, 
but  none  of  these  produce  an  equal  fall  of  temperature  unless  with  the 
presence  of  alarming  and  dangerous  symptoms.  Aconite  and  digitalis 
are  generally  supposed  to  reduce  the  temperature  through  their  effects 
on  the  circulation,  although  it  is  not  impossible  that  they  may  also 
affect  the  centres  for  heat  regulation.  Quinine  acts  probably  through 
reducing  the  metabolism,  and  alcohol  by  dilating  the  skin  capillaries, 
and  perhaps  by  lessening  the  movements  and  thereby  the  formation 
of  heat.  All  of  these  drugs  are  used  very  much  less  as  antipyretics 
now  than  formerly,  as,  besides  their  undesirable  secondary  effects,  the 
fall  of  temperature  is  less  certain  and  less  profound  than  under  the 
modern  antipyretics. 

The  antipyretics  are  also  used  very  largely  to  relieve  Neuralgic  Pain 
and  Headache,  often  with  complete  success.  So  little  is  known  re- 
garding the  pathology  of  these  diseases  that  it  would  seem  premature 
to  discuss  the  method  in  which  these  remedies  act.  By  many  they  are 
supposed  to  have  a  sedative  or  depressant  effect  on  the  central  nervous 
system,  but  this  must  be  limited  in  its  range,  for  quantities  sufficient 
to  remove  pain  often  leave  the  mind  perfectly  clear.  The  analgesic 
action  of  these  bodies  is  apparently  quite  different  from  that  of  mor- 
phine, for  in  many  instances  in  which  the  latter  is  successful  they  fail 
to  alleviate  the  condition.  On  the  other  hand  antipyrine  and  its  allies 
can  often  be  used  where  morphine  is  contraindicated,  either  from  the 
danger  of  the  habit  being  formed,  or  from  the  somnolence  it  induces. 
The  antipyretics  appear  to  be  of  little  or  no  value  in  relieving  the 
pain  caused  by  acute  inflammatory  conditions,  while  on  the  other  hand 
they  are  almost  specific  in  some  neuralgic  cases.  Almost  all  of  the 
antipyretics  are  efficient  in  these  cases,  but  larger  doses  are  generally 
required  than  to  reduce  fever,  and  the  more  powerful,  such  as  antifebrine, 
are  often  preferred  to  the  safer  and  more  slowly  acting  phenetidines. 
Caffeine  is  often  prescribed  along  with  the  antipyretic,  as  in  the 
compound  acetanilide  powder. 

Several  of  the  antipyretics  have  been  used  as  Substitutes  for  Quinine 
in  the  treatment  of  malaria,  but  none  of  them  seem  to  have  the  specific 
action  of  the  latter  on  the  organism  of  malaria,  and,  although  they  may 
reduce  the  temperature,  they  do  not  prevent  the  other  symptoms  and 
do  not  remove  the  cause  of  the  disease.  In  the  same  way  they  do  not 
seem  to  equal  salicylic  acid  in  efficiency  in  acute  rheumatism,  although 
here  again  they  reduce  the  temperature.  This  does  not  apply,  of 
course,  to  those  of  the  antipyretics,  such  as  malakine,  which  form 
salicylic  acid  in  their  decomposition  in  the  body.  It  is  to  be  noted 
that  the  amount  of  salicylic  acid  thus  formed  from  the  ordinary  dose 


384  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

of  the  antipyretics,  is  considerably  smaller  than  would  be  given  if  the 
acid  itself  were  prescribed. 

The  antipyretics  are  used  to  a  considerable  extent  in  cases  of  dia- 
betes insipidus  and  mellitus  and  appear  to  relieve  the  discomfort  and 
in  some  cases  to  improve  the  general  condition.  In  whooping  cough 
antipyrine  often  lessens  the  severity  of  the  attacks  and  also  renders 
them  less  frequent,  and  is  said  to  shorten  the  course  of  the  disease. 

The  use  of  antipyrine  and  other  members  of  this  series  as  sedatives  in 
hyperactivity  of  the  motor  functions  of  the  brain,  such  as  epilepsy  and 
chorea,  has  not  been  attended  with  great  success,  although  temporary  im- 
provement has  occasionally  been  noted,  as  after  so  many  other  remedies. 

Antipyrine  and  several  others  of  this  series  have  been  advocated  as  local 
sedatives  or  anEesthetics,  and  have  been  used  occasionally  to  lessen  the 
irritability  of  the  throat  and  larynx  and  thus  to  permit  of  the  minor  manipu- 
lations of  laryngology.  Holocaine,  a  body  closely  related  to  phenacetine, 
has  been  employed  to  a  limited  extent  as  a  local  anaesthetic  in  ophthalmol- 
ogy, but  appears  to  be  more  poisonous  than  other  equally  efficacious  drugs, 
such  as  eucaine. 

Thalline  has  been  advised  as  a  urethral  injection  in  gonorrhoea. 

The  occurrence  of  collapse  and  other  symptoms  has  led  to  a  consid- 
erable amount  of  distrust  of  the  antipyretics  among  many  of  the  med- 
ical profession.  In  justice  it  has  to  be  remembered  that  in  many  cases 
these  symptoms  were  produced  only  by  very  large  doses,  and  that 
since  experience  has  shown  that  beneficial  results  may  be  obtained  by 
smaller  quantities,  these  cases  have  notably  diminished  in  medical 
practice.  Unfortunately,  this  distrust  is  not  entertained  by  a  large 
class  of  the  laity,  and  numerous  cases  of  poisoning  arise  from  the  im- 
pression that  the  antipyretics  are  not  dangerous  drugs.  For  the  most 
part,  poisoning  seems  to  be  due  to  a  peculiar  sensitiveness  or  idiosyn- 
crasy, which  cannot  be  foreseen,  but  in  cases  of  great  exhaustion  and 
asthenia,  especially  when  accompanied  with  anemia,  these  drugs  have 
to  be  used  with  great  care  or  avoided  entirely'. 

BIBLIOGRAPHY. 

Umbach.     Arch.  f.  exp.  Path.  u.  Pharm., "xxi.,  p.  161. 

Riess.     Ibid.,  xxii.,  p.  127. 

Sawadowsky.     Centralbl.  f.  med. 'Wiss./ 1888,  p.  145. 

Martin.     Therap.  Gazette,  xi.,  1887,  p.  289. 

Lepine  u.  Porteret.     Comptes  rendus,  cvi.,  p.  1023,  and  cvii.,  p.  416. 

Jaffe  u.  Hilbert.     Ztschr.  f.  physiol,  Chem.,  xii.,  p.  295. 

Morner.     Ibid.,  xiii.,  p.  12. 

Loewi.     Ergeb.  der  Physiologic,  iii.,  1,  p.  365. 

Nencki.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxx.,  p.  306. 

v.  Mering.     Therap.  Monats.,  1893,  p.  577. 

Hinsberg  u.  Treupel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiii.,  p.  216. 

Treupel.     Deutsch.  med.  Woch.,  1895,  p.  222. 

Pellacani.     Arch.  Italien.  de  Biologic,  viii.,  p.  76. 

Lepine.    Kevue  de  Medicine,  1887,  p.  306. 

(John  u.  Hepp.     Berl.  klin.  Woch.,  1887,  p.  4. 

Filehne,  Liebermeister,  etc.     Congress  f.  inn.  Med.,  1885,  pp.  118-185  ;  1896,  pp.  3-100. 

Kumagawa.     Virchow's  Arch.,  cxiii.,  p.  134. 

Hinsberg  u.  Kast.     Centralbl.  f.  d.  med.  Wiss.,  1887,  p.  145.     (Phenacetine.) 

Maass.     Zts.  f.  klin.  Med.,  xxviii.,  p.  139.     (Analgen.) 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  385 

Filehne.     Berl.  klin.  Woch.,  1882,  p.  681 ;  1883,  p.  77. 

Stern.     Zts.  f.  klin.  Med.,  xx.,  p.  82. 

Hildebrandt.     Virchow's  Arch.,  cxxi.,  p.  1. 

Eichter.     Ibid.,  cxxiii.,  p.  118. 

C.  Rosenthal,     Arch.  f.  Anat.  u.  Phys.,  1888,  p.  1. 

W.  Rosenthal.     Ibid.,  1893,  Suppl.,  p.  243. 

Simon  and  Hock.     Johns  Hopkins  Hospital  Bulletin,  1890. 

Maragliano.     Ztschr.  f.  klin.  Med.,  xvii.,  p.  291,  and  xiv.,  p.  309. 

Evans.     Therap.  Gaz.,  1887,  pp.  237  and  379. 

Gottlieb.     Arch.  f.  exp.  Path.,  xxvi.,  p.  419,  and  xxviii.,  p.  167. 

Kraus.     Wien.  klin.  Woch.,  1894,  pp.  229  and  275. 

Harnack.     Therap.  Monats.,  1894,  p.  101. 

Fraenkel.     Zts.  f.  klin.  Med.,  xvii.,  Suppl.,  p.  239.     (Pyrodine.) 

E-iedel.     Zts.  f.  Heilkunde,  xvL,  p.  55. 

Penzoldt.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi.,  p.  313. 

Liepelt  u.  Stuhlinger.     Ibid.,  xh'ii.,  pp.  151  and  168. 

Tappeiner.     Ibid.,  xxviii.,  p.  295,  and  xxx.,  p.  231. 

Heinz.     Virchow's  Arch.,  cxxii.,  p.  112. 

Schutze.    Zeitschr.  f.  Hygiene,  xxxviii.,p.  205. 

Beniasch.     Zeitschr.  f.  klin.  Med.,  xlv.,  p.  51. 

Laivrow.     Zeitschr.  f.  phys.  Chemie,  xxxii.,  p.  111. 

Riethus.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv.,  p.  239. 

XXIV.     ANTISEPTICS  OF  THE   AROMATIC  SERIES  (CAR- 
BOLIC  AND   SALICYLIC   ACID   SERIES). 

Various  balsams  and  wood-tar  and  some  of  its  derivatives  have  long 
enjoyed  a  certain  reputation  in  surgery,  but  the  true  value  of  the 
bodies  of  the  aromatic  series  has  only  been  realized  since  the  systematic 
treatment  of  wounds  with  antiseptics  was  introduced  by  Lister  some 
thirty  years  ago.  The  first  antiseptic  proposed  by  him  was  carbolic 
acid,  and  this  held  its  position  for  several  years,  when  it  was  discovered 
that  bodies  of  similar  origin,  and  others  of  entirely  different  composi- 
tion possessed  equally  great  advantages  as  antiseptics  with  less  liability 
to  induce  poisoning.  Of  late  years  a  very  large  number  of  antiseptics 
belonging  to  the  aromatic  chemical  series  have  been  introduced,  and 
have  been  discarded,  often,  it  would  appear,  without  sufficient  exami- 
nation. It  is  not  within  the  scope  of  such  a  work  as  this  to  examine 
all  of  these,  especially  as  the  effects  of  many  of  them  differ  only  in 
detail,  but  the  chief  active  principles  will  be  mentioned. 

The  great  mass  of  the  aromatic  antiseptics  are  obtained  from  coal- 
or  wood-tar  by  more  or  less  complicated  reactions,  and  are  often  known 
as  the  coal-tar  or  tar  antiseptics. 

The  hydrocarbons  benzene  or  benzol,  tolvol,  xylol  are  too  volatile  for  use  as 
antiseptics,  and  the  only  hydrocarbon  used  for  this  purpose  is  Naphtalin(C10H8). 

Among  the  hydroxyl  compounds  of  benzol,  Carbolic  Acid  or  Phenol 
(C6H5OH)  is  the  best  known.  The  clioxybenzols  (C6H4(OH)2),  three  in  num- 
ber, hydroquinone,  pyrocatecftin,  and  resorcin  have  also  been  used  in  medicine, 
and  resorcin  was  at  one  time  a  popular  antiseptic,  although  it  has  latterly 
fallen  into  disuse. 

Among  the  trioxybenzols,  Pyrogallol  (C6H3(OH)3)  alone  has  been  used 
extensively  as  an  antiseptic  in  skin  diseases,  and  is  still  considered  of  value 
in  certain  conditions. 

Hydroxyl  derivatives  of  other  hydrocarbons  are  the  two  Naphtols,  a-  and 
j3-,  (C10H7OH)  which  are  used  as  intestinal  disinfectants.  Thymol  (C6H3(CH3)- 

25 


386  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

(C3H7)OH),  obtained  from  thyme,  was  introduced  as  a  substitute  for  carbolic 
acid,  but  has  fallen  into  disuse.  More  recently  the  cresols,  C6H4(OH)(CH3), 
of  which  three  are  known,  have  attained  some  prominence  as  antiseptics. 

The  phenol  ethers,  anisol  and  phenetol  (C6H5OCH3  and  C6H5OC2H5)  have 
never  been  introduced  into  therapeutic  use,  but  guaiacol  (CLH4(OH)(OCH8)), 
the  methyl  ether  of  pyrocatechin ,  has  had  some  use  of  late  years  as  an 
antiseptic  and  antipyretic.  A  combination  of  guaiacol  and  carbonic  acid 
known  as  guaiacol  carbonate  (CO(OC6H4OCH3)2)  has  also  been  used.  Other 
dioxy-derivatives  are  the  creosols  (C6H3(CH3)(OH)(OCH3)),  which  are  im- 
portant constituents  of  wood-tar  and  of  creosote. 

The  substitution  of  chlorine  for  hydrogen  in  the  benzol  ring  seems  to  in- 
crease its  antiseptic  power,  and  monochlorphenol  (C6H4C1OH)  and  trichlor- 
phenol  (C6H2C13OH)  have  been  suggested  as  antiseptics.  A  similar  intensified 
action  is  obtained  by  the  substitution  of  chlorine  in  the  members  of  the 
methane  narcotics.  (See  page  129.) 

The  presence  of  the  carboxyl  group  ( — COOH)  lessens  the  poisonous  action 
of  the  aromatic  series  exactly  as  in  the  case  of  the  methane  series.  Several 
acids  have  been  suggested  as  internal  antiseptics,  therefore,  and  one  of  them, 
Salicylic  acid  (C6H4OHCOOH),  is  perhaps  the  most  important  of  all  the  benzol 
compounds  at  the  present  time.  Benzole  acid  (C6H5COOH)  is  an  equally 
powerful  antiseptic,  but  is  comparatively  seldom  used  as  such.  It  is  the 
chief  constituent  of  several  of  the  ll  balsams,"  in  which  it  is  often  accom- 
panied by  cinnamic  acid  (C6H5CH=CHCOOH). 

Salicylic  acid  is  the  only  one  of  three  isomeric  acids  that  has  been  found  of 
value.  It  is  used  either  as  the  pure  acid  or  more  frequently  as  the  Salicylate 
of  Sodium,  or  in  the  form  of  an  ester.  One  of  these,  methylsal  icy  late,  has  long 
been  known  as  the  oil  of  wintergreen  and  as  sweet  oil  of  birch.  Another  well- 
known  ester  is  the  phenyl  salicylate  or  Salol,  (C6H4OHCOOC6H5),  while 
others  of  less  widespread  reputation  are  cresalol  (salicylate  of  cresol),  betol 
(salicylate  of  /3-naphthol),  salithymol  (salicylate  of  thymol).  Several  other 
salicylic  compounds  are  used  as  antipyretics  as  well  as  for  their  action  as 
salicylates  and  are  mentioned  among  the  antipyrine  series.  (Page  874.) 
The  most  recent  substitute  for  salicylic  acid  is  aspirin  or  acetylsalicylic  acid 
(C6H4OC2H3O.COOH). 

Another  acid  which  has  been  used  as  a  substitute  for  salicylic  acid  is 
cresotinic  acid  (C6H3(CH3)(OH)(COOH)),  and  the  oxynaphtoic  acids  (C10H6(OH)- 
(COOH))  have  been  suggested  as  antiseptics. 

Instead  of  carboxyl,  the  sulphon  radicle  has  been  attached  to  phenol  in 
order  to  lessen  its  toxicity,  and  in  this  way  the  so-called  sulphocarbolates 
were  formed.  They  must  be  distinguished  from  the  ether-sulphuric  acids 
or  double  sulphates  in  which  the  — HSO3  is  attached  to  the  carbon  of  the 
ring  by  oxygen,  while  in  the  sulphocarbolates  the  connection  between  the 

OTT 
sulphur  and  the  carbon  is  direct.     (Sulphocarbolate  of  sodium,  C6H4<Qn  ^ 

sodium-phenol  double  sulphate,  C6H5OSO3Na.)  3U8JNa, 

When  two  hydrogen  atoms  of  the  benzol  molecule  are  substituted  by 
other  elements  or  radicles,  three  different  chemical  products  may  result, 
and  these  are  known  as  ortho-,  meta-  or  para-compounds,  according  to  the 
relation  the  two  substituted  atoms  bear  to  each  other.  These  three  isomeric 
forms  very  often  differ  in  toxicity  and  also  in  their  antiseptic  power,  but  no 
general  statement  can  be  made  as  to  their  relative  position,  for  the  ortho- 
compound  is  sometimes  the  most  powerful  antiseptic,  as  in  salicylic  acid ; 
in  others  the  meta-compound,  as  in  metacresol,  while  parachlorphenol  is 
more  strongly  antiseptic  than  either  ortho-  or  metachlorphenol. 

Many  crude  preparations  of  these  bodies  are  still  in  use  and  have  the  ad- 
vantage of  cheapness  over  the  pure  principles,  and  are  therefore  preferred 
where  disinfection  has  to  be  carried  out  on  a  large  scale. 

Wood-tar  varies  in  its  composition  with  the  wood  from  which  it  is  ob- 
tained. The  most  important  constituents  are  generally  guaiacols  and  creo- 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  387 

sols  and  their  homologues,  while  carbolic  acid  and  the  cresols  are  less 
largely  represented.  Along  with  other  only  partially  known  substances, 
some  hydrocarbons  and  acids  such  as  acetic  acid,  also  occur. 

Creosote  is  obtained  from  beech  tar  and  consists  chiefly  of  guaiacol  and 
creosols  with  very  little  carbolic  acid  or  cresol,  which  latter  have  a  lower 
boiling  point  and  are  removed  in  the  course  of  preparation. 

The  volatile  or  ethereal  oils  have  also  antiseptic  properties,  and,  in  fact,  no 
line  of  demarcation  can  be  drawn  between  the  volatile  oil  series  and  the 
antiseptics  proper,  for  many  bodies  occur  in  both  groups,  and  the  great 
majority  of  the  constituents  of  the  volatile  oil  series  belongs  to  the  benzol 
compounds.  The  earliest  antiseptics  known  were  those  occurring  in  plants, 
as  is  shown  by  the  use  of  various  herbs  in  embalming  in  Egypt.  In  later 
times  several  of  the  balsams,  which  contain  benzoic  and  cinnamic  acids  dis- 
solved in  volatile  oils,  were  credited  with  beneficial  effects  in  the  treatment 
of  wounds. 

Ichthyol  is  the  ammonia  salt  of  a  sulphonic  acid  derived  from  the  tar  of  a 
bituminous  shale  which  is  found  in  the  Tyrol,  and  which  contains  the  re- 
mains of  many  fossil  fishes.  The  constitution  of  ichthyol  is  still  doubtful  and 
it  is  even  undecided  whether  it  is  not  really  a  mixture  of  a  number  of  bodies. 
It  contains  a  high  percentage  of  sulphur,  which  seems  to  be  only  in  part  in 
the  form  of  sulphons,  in  part  in  tha  of  mercaptans  and  sulphides.  Thiol  is 
an  artificial  product  formed  as  a  substitute  for  ichthyol  by  the  action  of  sul- 
phur and  afterwards  of  sulphuric  acid  on  the  tar  obtained  from  brown  coal. 
It  seems  to  consist  chiefly  of  sulphons,  and  is  very  soluble  in  water.  Tumenol 
is  another  artificial  substitute  for  ichthyol.  Naphtalan  is  prepared  from  raw 
naphtha  by  distillation  and  is  used  instead  of  ichthyol. 

Action. — The  simpler  bodies  of  the  aromatic  series  produce  symptoms 
in  the  living  organism  which  present  great  similarity  in  their  general 
features,  although  they  differ  in  details.  As  a  general  rule  it  is  found 
that  the  simpler  members  of  the  series  are  much  more  poisonous  to  the 
higher  animals  than  the  more  complex  ones,  while  the  latter  are  equally 
or  more  efficient  as  poisons  in  the  lowest  living  forms.  They  are  all 
possessed  of  a  more  or  less  marked  action  on  the  central  nervous  sys- 
tem, which  is  entirely  different  from  that  of  the  methane  narcotics, 
however.  The  brain  and  spinal  cord  are  thrown  into  a  condition  of 
abnormal  irritability,  which  is  betrayed  by  an  increase  in  the  reflex 
movements  and  tremor  and  convulsions,  and  which  is  not  due  to  the 
removal  of  inhibition  as  in  the  case  of  the  methane  compounds.  Later, 
a  stage  of  prostration  and  collapse  is  developed,  which  may  simulate  that 
seen  in  the  narcosis  of  the  fatty  series,  but  does  not  seem  to  be  identi- 
cal with  it,  for  though  in  man  the  consciousness  is  often  lost  in  this 
stage,  the  collapse  in  animals  is  in  many  cases  not  accompanied  by  loss 
of  sensation  or  of  the  voluntary  movements.  The  symptoms  are  gen- 
erally those  of  great  muscular  weakness  and  indicate  depression  of  the 
vital  centres  of  the  medulla  oblongata  and  of  the  heart  rather  than 
complete  loss  of  the  cerebral  functions.  They  resemble  surgical  shock 
more  than  the  anesthesia  following  the  use  of  chloroform  and  ether, 
and  are  probably  of  a  different  nature  from  the  latter. 

Many  of  the  members  of  the  benzol  series  tend  to  destroy  the  red 
cells  of  the  blood  and  to  form  methaemoglobin ;  this  effect  is  especially 
developed  in  the  case  of  pyrogallol  and  will  be  described  under  it  in 
detail.  Most  of  these  antiseptics  reduce  the  temperature  in  fever, 


388  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

while  they  have  little  effect  on  that  of  the  normal  body  unless  when 
given  in  large  enough  quantities  to  produce  collapse.  The  cause  of 
the  fall  of  temperature  in  fever  under  the  action  of  these  drugs  is  not 
satisfactorily  explained,  although  it  seems  probable  that  the  process  is 
the  same  as  in  the  antipyrine  series,  with  which  they  are  nearly  allied. 
The  aromatic  poisons  differ  from  the  typical  members  of  the  methane 
series  in  their  effects  on  protoplasm  in  general.  Alcohol  and  ether 
destroy  life  in  all  forms  of  protoplasm  when  they  are  brought  in  con- 
tact with  it  in  sufficient  concentration,  but  the  phenols  and  acids  of 
the  aromatic  series  do  so  in  more  dilute  solutions,  and  in  fact  owe 
their  importance  in  medicine  to  their  activity  as  general  protoplasm 
poisons. 

Small  quantities  of  the  aromatic  bodies  seem  to  increase  the  activity  of 
living  matter,  at  any  rate  under  some  conditions,  for  the  alcoholic  fermen- 
tation is  said  to  be  accelerated  by  the  presence  of  minute  proportions  of  these 
poisons,  and  in  the  higher  animals  some  of  them  increase  the  nitrogenous 
metabolism,  while  larger  doses  destroy  the  yeasts  and  also  the  tissues  of  the 
body.  The  evidence  of  central  nervous  irritation  might  also  be  cited  in 
support  of  the  view  that  the  members  of  the  aromatic  series  first  accelerate 
and  then  retard  protoplasmic  activity,  but  the  evidence  is  too  limited  as  yet 
to  admit  of  such  a  generalization. 

Therapeutic  Uses.  —  The  members  of  the  aromatic  series  are  used  in 
therapeutics  chiefly  as  disinfectants  and  antiseptics,  that  is,  to  destroy 
or  retard  the  growth  of  pathogenic  and  putrefactive  microorganisms 
and  yeasts.  Their  introduction  by  Lister  to  prevent  the  infection  of 
wounded  surfaces  in  surgery  was  followed  by  a  revolution  in  surgical 
methods,  which  can  only  be  paralleled  by  that  which  followed  the  in- 
trod  uction  of  ansesthetics  some  twenty  years  earlier. 

The  successful  treatment  of  local  infections  by  means  of  antiseptics 
encouraged  the  hope  that  general  septic  diseases  might  be  as  favorably 
influenced  by  them,  but  the  two  conditions  are  obviously  entirely  dif- 
ferent, for  in  the  case  of  a  local  infection  the  remedy  may  be  applied 
at  the  diseased  point,  and,  although  it  may  destroy  the  life  of  the 
superficial  cells  in  the  neighborhood,  this  is  not  of  vital  importance. 
On  the  other  hand,  a  disinfectant,  acting  throughout  the  tissues  of  the 
body  in  sufficient  quantity  to  destroy  the  microbes  of  infection,  must 
have  an  equally  unfavorable  effect  on  the  cells  of  the  host,  unless  it 
has  a  specific  action  on  the  parasite,  and  this  is  very  exceptional. 

A  disinfectant  in  the  strict  use  of  the  term  is  a  substance  used  to 
destroy  microbes,  while  an  antiseptic,  while  not  actually  killing  the 
germs,  prevents  their  growth  as  long  as  it  remains  in  contact  with  them. 
A  disinfectant  is  accordingly  only  intended  to  act  for  a  short  time,  for  if 
the  infected  matter  be  once  rendered  sterile  it  can  only  become  dan- 
gerous by  being  again  contaminated.  For  example,  a  room  requires 
only  to  be  disinfected  after  a  case  of  infectious  disease.  A  wound,  on 
the  other  hand,  even  though  completely  disinfected  may  become  con- 
taminated again  very  easily  and  an  antiseptic  may  be  required  to  prevent 
the  further  growth  of  microbes.  Many  substances  are  disinfectant  in 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  389 

large  quantities  and  antiseptic  in  more  dilute  solutions,  but  others  are 
too  weak  to  disinfect  thoroughly  though  they  retard  the  growth  of 
pathogenic  organisms,  and  still  others  may  be  employed  to  disinfect 
but  are  unsuitable  for  use  as  antiseptics,  either  because  they  are  too 
poisonous  to  be  applied  for  a  sufficient  time  or  because  they  lose  their 
effects  on  the  microbes  (peroxide  of  hydrogen  group).  • 

The  uses  of  the  antiseptics  and  disinfectants  may  be  stated  as  follows  : 

1.  To  Disinfect  Rooms,  Furniture,  Clothes,  etc.  —  For  these  purposes, 
the  strongest  and  cheapest  drugs  which  do  not  actually   injure  the 
objects  may  be  employed.     None  of  the  aromatic  series  is  very  trust- 
worthy   here,    although    carbolic   solution    has  been  employed ;    the 
gaseous  disinfectants,  formaldehyde  and  sulphurous  acid,  are  much  more 
efficient.     For  the  disinfection  of  the  excrementa,  crude  carbolic  acid 
and  tar  have  been  advocated. 

2.  To  Prevent  the  Infection  of  Wounds  in  surgery.     This  was  first 
attained  by  Lister's  carbolic  acid  dressing  and  operative  procedure, 
but  many  other  antiseptics  have  since  been   substituted  for  carbolic 
acid,  and  the  use  of  antiseptics  during  operations  on  uninfected  organs 
has  given  \vay  to  the  aseptic  method.     For  use  during  operations  on 
infected  wounds,  the  disinfectant  must  be  soluble  or  miscible  in  water, 
and  ought  to  produce  as  little  irritation  as  possible,  but  there  is  less 
likelihood  of  serious  poisoning  or  irritation  from  the  use  of  antiseptics 
here  than  from  their  subsequent  application  to  the  wounded  surface  as 
dressings.     The  importance  of  avoiding  the  use  of  irritant  antiseptics 
in  operations  on  delicate  structures,  such  as  the  peritoneum,  has  only 
been  fully  recognized  of  late  years.     Where  a  dressing  has  to  be  applied 
for  some  time,  and  especially  when  the  wounded  surface  is  large,  as  in 
the  case  of  burns  or  large  abscesses,  the  danger  of  absorption  has  to  be 
taken  into  consideration,  and  antiseptics  ought  therefore  to  be  chosen 
which  are  either  absorbed  slowly  or  are  not  very  poisonous  to  man. 
The  frequent  occurrence  of  more  or  less  severe  carbolic  intoxication 
has  led  to  its  employment  being  much  more  restricted  than  formerly, 
while  the  less  soluble  or  less  poisonous  antiseptics  have  taken  its  place. 

3.  In  the  Treatment  of  Skin  Diseases  the  danger  of  absorption  is  even 
greater  than  in  the  dressing  of  wounds,  as  the  absorbing  surface  is  often 
very  much  more  extensive,  and  in  addition  the  more  irritant  antiseptics 
are  obviously  not  admissible  here.     In  many  cases  of  successful  treat- 
ment with  bodies  of  the  aromatic  series,  the  remedy  seems  to  act  not  only 
as  an  antiseptic  but  also  as  a  rnild  irritant  and  astringent.     Pyrogallol 
is  believed  by  some  dermatologists  to  be  of  value  only  from  its  reduc- 
ing action  depriving  the  superficial  tissues  of  their  oxygen. 

4.  The  antiseptics  have  been  frequently  employed  for  their  Disin- 
fectant Action  on  the  Bowel,  and  as  far  as  the  putrefaction  of  the  in- 
testinal contents  is  concerned,  with  success.     The  disintegration  of  the 
food  by  microbes  in  the  bowel  may  be  estimated  by  the  amount  of 
double  sulphates  appearing  in  the  urine,  and  in  several  series  of  exper- 
iments these  have  been  found  to  be  notably  diminished  by  bodies  of 
the  aromatic  series.     Fewer  microbes  have  been  found  in  the  faeces 


390  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

also  after  these  antiseptics  have  been  administered.  When,  however, 
bacterial  infection  of  the  wall  of  the  bowel  is  treated  with  these  anti- 
septics, the  results  are  less  favorable.  In  typhoid  fever,  in  which  the 
subject  has  been  most  frequently  examined,  the  number  of  the  typhoid 
bacilli  in  the  stools  has  not  been  lessened  to  any  noticeable  extent,  and 
the  majority  of  clinical  observers  seem  to  be  very  sceptical  as  to  any 
relief  of  the  symptoms  being  attained  or  of  the  duration  of  the  dis- 
ease being  shortened  by  their  use. 

Any  drug  used  for  the  disinfection  of  the  intestine  must  not  be  irri- 
tant, nor  very  poisonous.  It  must  not  be  too  soluble,  since  otherwise 
it  may  be  absorbed  from  the  stomach  and  fail  to  reach  the  bowel,  and 
on  the  other  hand  it  must  be  soluble  to  some  extent,  or  it  cannot  mix 
very  intimately  with  the  contents  of  the  intestine.  Carbolic  acid  is 
scarcely  fitted  for  this  purpose,  for  it  irritates  the  stomach  and  is  also 
rapidly  absorbed.  Some  of  the  cresols  have  been  recommended  of  late 
years,  and  the  naphtalin  preparations  have  also  enjoyed  some  repu- 
tation. Salol  and  its  congeners  have  the  advantages  of  being  almost 
completely  insoluble  and  harmless  in  the  stomach  and  of  being  dis- 
solved and  rendered  active  by  the  intestinal  juices,  and  have  been 
found  of  value  in  excessive  putrefaction  of  the  contents  of  the  bowel. 
It  has  to  be  added  that  putrefaction  in  the  bowel  is  best  treated  by  its 
evacuation  by  a  purgative,  such  as  one  of  the  mercurial  preparations, 
which  also  have  a  high  antiseptic  value. 

5.  The  antiseptics  of  the  benzol  series  are  excreted  in  great  part  by 
the   kidneys,  and   the  urine  is   thus   rendered  weakly  antiseptic  and 
irritant.     This  fact  has  been  taken  advantage  of  in  the  treatment  of 
Septic  Diseases  of  the  Bladder  and  Urethra ;  the  drugs  used  for  this  pur- 
pose must  not  be  too  irritant  to  the  gastric  mucous  membranes,  and 
must  be  easily  absorbed,  and  not  dangerously  poisonous.     Here,  again, 
salol  has  been  found  of  value  as  well  as  salicylic  acid.     The  forms  in 
which  the  benzol  derivatives  are  excreted  by  the  kidney  are  generally 
much  less  irritant  and  antiseptic  than  that  in  which  they  are  adminis- 
tered.    In   estimating  the  value  of  each  as  a  urinary  disinfectant,  it 
must  also  be  remembered  that  many  of  them  are  liable  to  undergo 
oxidation  in  the  urine  itself.     (See  also  copaiba  series  and  urotropin.) 

6.  Small  quantities  of  some  of  the  more  volatile  members  of  this  series, 
especially  of  the  hydrocarbons,  escape  by  the  lungs,  and  this  has  led 
to  their  use  in  Pulmonary  Disease,  especially  in  phthisis.     It  may  be 
stated  at  once  that  careful  observers  are  almost  all  united  in  the  belief 
that  the  internal  administration  of  these   remedies  has  practically  no 
antiseptic  effect  on  the  microbes  in  the  lungs.     Some  relief  is  often  ob- 
tained, but,  it  is  believed,  only  through  their  disinfectant  action  in  the 
stomach  and  bowel.     Antiseptic  remedies  have  also  been   inhaled  in 
vapor  or  spray  and  have  been  injected  into  the  trachea  and  even  into 
the  lung  directly,  but  as  far  as  the  tubercle  bacillus  is  concerned,  they 
have  had  no  result  in  the  hands  of  the  vast  majority  of  physicians.     In 
cases  of  gangrene  of  the  lung,  foetid  bronchitis,  etc.,  the  inhalations  re- 
lieve the  patient  to  some  extent,  and  certainly  lessen  the  offensive  odor. 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  391 

7.  The  use  of  antiseptics  to  Destroy  Pathogenic  Germs  in  the  Tissues 
after  Absorption  is  very  limited.  It  is  now  recognized  to  be  hopeless  to 
attempt  to  find  a  single  body  which  will  destroy  all  forms  of  bacteria  in 
the  tissues,  while  leaving  the  host  uninjured,  but  there  is  still  reason 
to  believe  that  in  the  future  specific  antiseptics  may  be  found  for  at 
least  some  of  the  constitutional  diseases.  Such  a  specific  action  is 
seen  in  the  effects  of  quinine  on  the  organism  of  malaria,  of  salicylic 
acid  in  rheumatic  fever,  and  of  mercury  in  syphilis,  all  of  these  ap- 
parently acting  more  strongly  on  the  cause  of  the  disease  than  on  the 
tissues  of  the  patient.  While  it  may  be  hoped  that  the  antiseptic 
treatment  of  internal  maladies  has  not  reached  its  final  limit,  the  only 
constitutional  disease  in  which  the  aromatic  series  has  been  shown  to 
be  of  incontestable  value  is  acute  rheumatism,  and  in  many  other 
conditions  which  were  formerly  treated  with  benzol  antiseptics,  they 
have  proved  rather  injurious  than  otherwise.  Renewed  interest  has 
been  aroused  in  this  question  recently  by  the  proposal  to  treat  septic- 
aemia by  the  intravenous  injections  of  antiseptics,  but  investigation  has 
shown  that  even  the  least  dangerous  cause  symptoms  of  poisoning  in 
much  smaller  quantities  than  would  be  necessary  to  render  the  blood 
an  antiseptic  solution. 

There  is  reason  to  believe  that  solutions  containing  several  of  the 
benzol  series  are  more  strongly  antiseptic  than  those  containing  an 
equal  percentage  of  the  individual  pure  bodies,  and  that  the  mixture 
of  such  a  body  as  carbolic  acid  with  an  antiseptic  of  another  kind, 
e.  g.,  mercuric  perchloride,  is  still  more  efficient  than  the  correspond- 
ing proportion  of  either  alone.  This  appears  to  be  due  to  a  change  in 
the  solubility  of  the  disinfectant,  at  any  rate  in  some  cases.  If  a 
poison  is  to  penetrate  into  the  interior  of  an  organism  in  quantity  it 
must  be  as  soluble  in  the  protoplasm  as  in  the  fluid  in  which  it  is  ap- 
plied, for  it  is  obvious  that  it  will  not  leave  a  medium  in  which  it  is 
readily  soluble  for  one  in  which  it  is  dissolved  with  difficulty.  Ac- 
cordingly it  is  found  that  fats  and  oils  in  which  the  members  of  the 
aromatic  series  are  very  soluble  are  not  suitable  as  media  for  their  ap- 
plication, for  the  poisons  remain  in  the  oily  menstruum  and  fail  to 
penetrate  the  microbes  in  which  they  are  less  soluble.  On  the  other 
hand,  the  addition  of  inorganic  salts  to  an  aqueous  solution  of  carbolic 
acid  often  increases  its  antiseptic  power,  because  the  poison  becomes 
less  soluble  in  the  water  and  shows  a  greater  tendency  to  escape  from 
it  into  the  interior  of  the  microbes. 

Fate  in  the  Tissues. — The  fate  of  the  members  of  the  aromatic  series 
in  the  body  is  very  uniform  in  one  respect  —  the  benzol  ring  is  rup- 
tured only  with  great  difficulty.  In  the  great  majority  of  cases  the 
changes  which  these  substances  undergo  in  the  tissues  affect  only  the 
hydrogen  or  the  side  chains  attached  to  the  carbon  atoms,  and  leave 
the  form  in  which  these  last  are  attached  to  each  other  unchanged. 
The  chief  exceptions  to  this  rule  are  pyrogallol  and  gallic  acid,  which 
seem  to  undergo  more  or  less  complete  oxidation  to  carbonic  acid  and 
water.  Some  oxidation  takes  place  in  the  aromatic  series,  however, 
the  simpler  forms,  such  as  benzol  and  aniline,  tending  to  form  hydroxyl 


392  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

compounds,  while  those  with  a  side  chain  formed  of  methane  deriva- 
tives tend  to  oxidize  it  to  carboxyl.  The  oxidation  of  the  benzol  com- 
pounds in  the  tissues  therefore  results  in  the  formation  of  oxybenzols 
and  aromatic  acids,  and  this  oxidation  is  probably  not  limited  to  any 
one  particular  tissue  or  organ.  These  bodies  are  not,  however,  ex- 
creted in  this  form  in  ordinary  cases,  but  enter  into  secondary  combi- 
nations in  which  they  appear  in  the  urine.  The  hydroxyl  bodies 
unite  with  sulphuric  and  glycuronic  acids  to  form  double  sulphates 
(ether-sulphuric  acid  salts)  and  glycuronates,  while  the  aromatic  acids 
are  excreted  in  combinations  with  glycocoll,  which  are  known  as  hip- 
puric,  salicyluric,  etc.,  acids.  The  last  synthesis  probably  occurs 
chiefly  in  the  kidney,  while  the  double  sulphates  are  said  to  be  formed 
in  the  liver. 

A  few  examples  of  the  changes  undergone  in   the  tissues  may  elu- 
cidate   the  above  statement.     Benzol   (C6H6)   is  oxidized  to  phenol 

(C6H5OH),  and  to  dioxybenzols  lC6H4<^H  )  ,  which  combine  in  the 

kidney  with  sulphuric  and  glycuronic  acids  to  form  phenol-sulphuric 
(C6H5O  —  SO3H)  and  phenol-glycuronic  acids,  and  the  correspond- 
ing dioxybenzol  compounds.  Toluol  (C6H5  —  CH3)  is  oxidized  to 
benzoic  acid  (C6H5  —  COOH),  which  combines  with  the  glycocoll  of 
the  body  to  form  hippuric  acid  (C6H5CO—  NHCH2COOH).  Xylol 

V 

I  is  oxidized  only  in  one  side  chain  and  forms  toluic  acid 

,  which  is  excreted  in  combination  with  glycocoll  as 


toluric  acid. 

Although  a  general  resemblance  exists  in  the  oxidation  products  of 
these  bodies  in  the  tissues  and  in  the  forms  in  which  they  are  excreted, 
considerable  differences  are  noted  in  the  details.  Thus,  naphtalin 
undergoes  the  same  oxidation  as  benzol,  forming  naphtol  in  place  of 
phenol,  but  while  the  phenol  appears  in  the  urine  in  combination  with 
sulphuric  acid  almost  entirely,  the  naphtol  combines  with  glycuronic 
acid  for  the  most  part. 

BIBLIOGRAPHY  . 

Consult  that  given  under  the  individual  members—  CABBOLIC  ACID,  SALICYCLIC 
ACID,  etc. 

Antiseptic  Action. 

Dougall.     Med.  Times  and  Gazette,  1872,  i.,  p.  495. 
Bucholtz.     Arch.  f.  exp.  Path.  u.  Pharm.,  iv.,  p.  1. 
Gerhardt.     Ergebnisse  der  Physiol.,  iii.,  1.,  p.  153. 
Fortescue-Brickdale.     Lancet,  1903,  i.,  p.  98. 
Mieczkowski.     Mit.  a.  d.  Grengebiet,  ix.,  p.  405. 
Koch.     Mittheilung  aus  dem  Kaiserlich.  Gesundheitsamt.,  i.,  p.  234. 
Jalan  de  la  Croix.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiii.,  p.  175. 
Cash.     Keports  of  British  Local  Government  Board,  1886. 
Stemberg.     Bull,  of  National  Board  of  Health,  1881. 
Schulz.     Pfluger's  Arch.,  xlii.,  p.  517. 
Biernacki.     Ibid.,  xlix.,  p.  112. 
Kronicj  u.  Paul.     Ztschr.  f.  Hygiene,  xxv.,  p.  1. 
Spiro  u.  Bruns.     Arch.  f.  exp.  Path.  u.  Pharm.,  xli.,  p.  353. 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  393 

General  Action. 

Brunton  and  Cash.     Proc.  Roy.  Soc.,  xlii.,  p.  240. 

Schuttzenu.  Graebe.     Arch,  t  Anat.  u.  Phys.,  1867,  p.  166. 

Schultzen  u.  Naunyn,     Ibid. ,  p.  349. 

Nencki.     Ibid.,  p.  399,  1870. 

Baumann.     Pfliiger's  Arch.,  xiii.,  p.  285. 

Baumann  u.  Preusse.     Arch.  f.  Anat.  u.  Phys.,  1879,  p.  245. 

Baumann  and  pupils.     Zts.  f.  phys.  Chem.,  i.-vii. 

Bokorny.     Pfliiger's  Arch.,  Ixiv.,  p.  306. 

Nencki  u.  Giacosa.     Zts.  f.  physiol.  Chem.,  iv.,  p.  325. 

Nencki.     Arch.  f.  exp.  Path.  u.  Pharm.,  i.,  p.  420;  xxx.,  p.  300. 

Karpow.     Arch,  des  Sciences  biolog.,  ii.,  p.  305. 

fiaglioni.     Ztschr.  f.  allg.  Phys.,  iv.,  p.  313. 

Steiff.     Zts.  f.  klin.  Med.,  xvi.,  p.  311. 

Binet.     Trav.  de  Labor,  de  Therap.  exp.  de  Geneve,  ii.,  p.  143. 

Schmiedeberg.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiv.,  p.  379. 

1.   Carbolic  Acid. 

Carbolic  acid  or  phenol,  the  first  of  the  modern  antiseptics  to  be  in- 
troduced, acts  like  the  rest  of  the  simpler  benzol  compounds  as  a 
General  Protoplasm  Poison,  although  in  the  vertebrates  it  acts  more 
powerfully  on  the  central  nervous  system  than  on  the  other  tissues. 

Its  poisonous  effects  are  well  seen  when  it  is  applied  to  unicel- 
lular  organisms  such  as  the  protozoa.  Even  dilute  solutions  cause 
immediate  arrest  of  all  movements  ;  the  organism  assumes  a  spherical 
shape  and  loses  its  transparency,  and,  unless  the  solution  be  very 
attenuated,  dies  in  the  course  of  a  few  minutes.  Plant  cells  are  acted 
on  in  the  same  way,  and  the  individual  cells  of  more  highly  organized 
animals,  such  as  the  ciliated  epithelium  of  the  air  passages  and  the 
spermatozoa,  are  killed  at  once  when  brought  in  contact  with  carbolic 
acid.  There  is  some  evidence,  however,  that  very  dilute  solutions  of 
carbolic  acid,  as  of  other  antiseptics,  tend  to  increase  the  activity  of 
protoplasm.  Thus  Biernacki  and  Schulz  have  found  that  while  solu- 
tions of  phenol,  such  as  are  used  as  surgical  antiseptics,  are  immediately 
fatal  to  the  yeast  plant,  very  dilute  solutions  increase  its  activity.  The 
effect  of  carbolic  acid  on  protoplasm  has,  however,  been  studied  chiefly 
in  the  bacteria.  Its  antiseptic  power,  while  always  considerable,  is 
found  to  vary  greatly  with  the  species  of  microbe.  Thus,  while  it  is 
fairly  poisonous  to  the  ordinary  pyogenic  organisms,  it  has  to  be  present 
in  very  concentrated  form  to  destroy  the  more  resistant  spores  of  an- 
thrax, and  like  other  antiseptics,  is  much  less  poisonous  to  the 
microbes  than  to  the  protozoa  and  other  simple  forms  of  life.  The 
development  and  reproduction  of  many  microorganisms  has  been  found 
to  be  much  delayed,  or  altogether  prevented,  as  long  as  they  remained 
in  a  solution  of  one  part  of  carbolic  acid  in  400—600  parts  water,  but 
in  order  to  kill  the  spores  very  much  more  concentrated  solutions  (5 
per  cent.)  were  required,  and  Koch  found  that  the  spores  of  the 
anthrax  bacilli  were  destroyed  by  5  per  cent,  carbolic  solution  only 
after  they  had  remained  in  it  for  two  days. 

It  seems  to  vary  considerably  in  its  action  on  the  unorganized  fer- 
ments ;  thus  it  is  said  not  to  retard  appreciably  the  fermentations 


394  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

produced  by  emulsin,  diastase  and  my  rosin,  even  when  present  in  the 
solution  up  to  5  per  cent.,  while  pepsin,  ptyalin  and  the  rennet  fer- 
ment are  weakened  by  somewhat  smaller  quantities. 

Carbolic  acid  precipitates  Proteids  in  solution  and  also  in  the  cells. 
It  does  not  seem  to  enter  into  any  such  firm  combination  with  them  as 
is  formed  when  tannic  acid  or  a  salt  of  one  of  the  heavy  metals  is  added 
to  a  solution  of  proteid,  for  it  can  be  washed  out  of  the  precipitate 
with  comparative  ease.  Its  action  in  precipitating  albumins  may 
rather  be  compared  to  that  of  alcohol,  in  which  the  proteid  is  precipi- 
tated, not  because  an  insoluble  compound  is  formed,  but  because  of  a 
change  in  the  nature  of  the  solvent.  It  results  from  this  that  carbolic 
acid  penetrates  more  thoroughly  than  the  metallic  antiseptics,  which 
are  rendered  insoluble  by  the  albumin  they  meet,  and  whose  action 
therefore  tends  to  remain  confined  to  the  surface. 

This  coagulation  of  the  proteids  occurs  whenever  carbolic  acid  is 
brought  in  contact  with  the  tissues.  On  the  Skin  a  white,  opaque  scar 
is  formed  by  concentrated  phenol,  which  becomes  red  and  shining  af- 
terwards and  then  falls  off  in  a  few  days,  leaving  a  light  brown  stain 
which  may  remain  for  several  weeks.  Even  a  five  per  cent,  solution 
applied  to  the  fingers  produces  tingling  and  warmth,  which  is  often  fol- 
lowed by  opacity  and  shrinking  of  the  epidermis  and  a  sense  of  numb- 
ness. This  numbness  may  amount  to  almost  complete  anaesthesia  if 
more  concentrated  solutions  are  applied,  no  pain  being  felt  even  when 
the  skin  is  cut  through.  When  applied  for  some  time  and  prevented 
from  evaporating,  carbolic  acid  may  cause  extensive  dry  gangrene  of 
the  part  from  its  penetrating  through  the  surface  layer  and  reaching  the 
deeper  tissues.  Applied  to  a  Wound  in  five  per  cent,  solution,  phenol 
induces  pain  and  irritation  and  the  formation  of  a  white  pellicle  of 
coagulated  proteids.  It  causes  irritation  and  necrosis  of  the  Mucous 
Membranes,  and  if  applied  in  sufficient  quantity  may  lead  to  sloughing 
and  acute  inflammation.  This  local  effect  may  prove  fatal  from  shock 
and  collapse  when  large  quantities  of  the  undiluted  acid  are  swallowed, 
the  eifect  resembling  exactly  that  produced  by  other  corrosive  sub- 
stances. 

Apart  from  its  local  action,  carbolic  acid  has  important  effects  after 
its  absorption  into  the  blood.  The  most  marked  of  these  are  the 
changes  in  the  Central  Nervous  System.  When  a  small  quantity  of 
carbolic  acid  is  injected  into  the  frog,  the  first  symptoms,  apart  from 
those  produced  by  the  pain  of  the  injection,  consist  in  an  unusual  quiet 
and  in  the  absence  of  the  spontaneous  movements.  Later,  quivering 
of  individual  muscles,  and  apparently  of  the  individual  bundles  of 
muscle  fibres,  sets  in,  and  this  is  soon  accompanied  by  an  increase  in  the 
reflex  irritability  and  eventually  by  convulsions  similar  to  those  seen 
after  strychnine.  These  movements  gradually  become  weaker,  and 
eventually  complete  paralysis  is  induced,  while  the  heart  continues  to 
beat  and  the  muscles  and  nerves  react  to  the  electric  shock.  A  dilute 
solution  of  carbolic  acid  applied  directly  to  the  exposed  spinal 
cord  paralyzes  the  sensory  elements  immediately,  while  leaving 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  395 

unaffected  the  motor  fibres  and  the  cells  of  the  anterior  horn  (Bag- 
lioni). 

In  mammals,  a  very  similar  set  of  symptoms  are  produced,  save  that 
there  is  often  no  noticeable  preliminary  stage  of  depression.  Some 
weakness  and  lethargy  may  be  present,  however,  and  are  followed  by 
marked  muscular  tremor,  which  resembles  the  shivering  produced  by 
cold.  At  intervals  this  is  interrupted  by  sudden  twitches  in  different 
muscles,  and  later  by  clonic  convulsions.  The  respiration  and  the 
pulse  are  at  first  accelerated,  but  afterwards  are  slow,  irregular,  and 
weak.  The  movements  become  feeble  and  appear  at  longer  intervals, 
the  respiration  is  shallow  and  irregular,  and  the  animal  passes  into  a 
condition  of  collapse,  in  which,  however,  the  sensibility  to  pain  is  often 
preserved.  Eventually  death  occurs  from  asphyxia.  After  very  large 
doses  the  collapse  may  be  immediate,  no  convulsions  being  observed, 
the  heart  and  respiration  often  ceasing  simultaneously.  In  most  cases 
salivation  is  a  marked  symptom,  and  the  temperature  often  falls  far 
below  the  normal. 

In  man,  convulsions  are  comparatively  rarely  seen.  When  large 
quantities  are  taken,  immediate  unconsciousness  may  result  and  death 
follow  within  a  few  minutes.  How  far  this  is  due  to  the  local  cor- 
rosion, and  how  far  the  direct  action  on  the  central  nervous  system  is 
involved,  cannot  be  determined.  In  more  gradual  poisoning,  de- 
pression and  weakness,  headache,  nausea  and  vomiting  are  followed  by 
giddiness,  noises  in  the  ears,  pallor  and  collapse,  with  irregular  pulse 
and  respiration,  and  cold  perspiration  ;  fainting  and  unconsciousness 
then  lead  to  failure  of  the  breathing,  and  death.  Delirium  and  excite- 
ment have  been  observed  in  some  cases.  Fatal  poisoning  may  arise 
from  swallowing  the  concentrated  or  dilute  solution,  or  from  absorption 
from  wounds  and  abscesses.  It  has  also  occurred  in  man  from  absorp- 
tion through  the  unbroken  skin. 

The  autopsy  sometimes  gives  no  special  indications  of  the  cause  of 
death,  save  the  local  corrosion  of  the  alimentary  canal.  Inflammation 
and  necrosis  of  the  intestine  is  said  to  have  been  observed  in  some 
cases  in  which  the  poison  was  absorbed  from  skin  wounds,  and  fatty 
degeneration  is  sometimes  induced  in  the  liver  and  the  renal  epithelium, 
but  is  not  constant. 

The  convulsions  in  the  frog  arise  from  an  increase  in  the  irritability 
of  the  spinal  cord,  especially  of  the  cells  of  the  anterior  horn  (Baglioni), 
for  they  are  not  arrested  by  section  of  the  medulla  oblongata.  In 
mammals  the  sudden  contractions  of  isolated  muscles  appear  due  to  a 
similar  action  on  the  spinal  cord,  but  the  clonic  convulsions  and  the 
persistent  tremors  are  probably  of  cerebral  origin,  and  Berkholz  found 
the  cerebral  cortex  abnormally  irritable  after  carbolic  acid.  The  rarity 
of  convulsions  in  man  has  not  been  satisfactorily  explained.  In  some 
cases  the  course  of  the  intoxication  is  too  short,  the  large  amount  of 
poison  swallowed  inducing  immediate  collapse,  while  in  others  their 
absence  may  be  due  to  the  debility  of  the  patient  from  disease ;  but 
in  a  considerable  number  of  cases  of  poisoning  in  which  neither  of 


396  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

these  conditions  was  present,  no  convulsions  were  observed.  A  sim- 
ilar contrast  between  the  effects  of  a  poison  on  the  lower  animals  and 
on  man  has  been  mentioned  already  under  morphine.  In  all  cases, 
the  primary  stimulation  of  the  central  nervous  system  is  followed  by 
depression  and  paralysis  if  large  doses  are  administered. 

The  acceleration  of  the  Respiration  and  of  the  Heart  seen  in  mam- 
mals has  been  supposed  to  be  an  indirect  result  of  the  increased  mus- 
cular movement  and  convulsions,  but  this  seems  to  be  incorrect,  for 
the  heart  is  found  to  be  accelerated  before  the  convulsive  movements 
and  tremor  appear,  and  the  frog's  heart  is  accelerated  in  cases  where 
no  movements  whatever  occur.  It  would  seem  probable  that  the 
acceleration  of  the  heart  is  due  to  direct  action  on  the  muscle  or  on 
the  regulating  nerves.  The  subsequent  slowing  is  undoubtedly  due  to 
muscular  action. 

The  acceleration  of  the  respiration  precedes  the  increased  move- 
ment also,  and  would  therefore  seem  to  be  due  to  action  on  the  med- 
ullary centre,  which  is  first  stimulated  and  later  paralyzed.  The 
vaso-motor  centre  is  said  by  Gies  to  be  depressed  at  once  by  the  injec- 
tion of  carbolic  acid  into  the  blood,  but  it  may  be  questioned  whether 
it  too  is  not  first  excited  when  the  poison  is  absorbed  more  slowly. 
It  is  undoubtedly  depressed  in  the  later  stages  of  poisoning,  and  this, 
together  with  the  weakness  and  slowness  of  the  heart,  causes  a  fall  in 
the  blood-pressure. 

The  peripheral  Nerves  and  Muscles  do  not  seem  to  be  affected  in 
general  poisoning  in  mammals,  although  in  the  frog  their  irritability 
and  the  capacity  for  work  of  the  muscle  may  be  somewhat  reduced. 

On  the  direct  application  of  solutions  of  carbolic  acid  to  the  nerves 
or  muscles,  these  are  at  once  killed,  like  other  forms  of  living  matter. 

The  increased  Secretion  of  saliva,  perspiration  and  tears  which  is 
seen  in  poisoning  in  mammals  is  probably  of  central  origin,  and  may 
possibly  be  associated  with  the  nausea  and  vomiting. 

The  fall  in  Temperature  in  carbolic  acid  poisoning  seems,  for  the 
main  part,  to  be  due  to  the  collapse,  although  it  is  impossible  to  state 
how  far  this  may  be  aided  by  some  alteration  of  the  regulating  func- 
tion, such  as  is  seen  in  the  closely  related  group  of  the  antipyretics. 

Carbolic  acid  added  to  the  defibrinated  Blood  leads  to  the  slow  forma- 
tion of  methsemoglobin,  but  this  does  not  occur  in  the  living  animal. 
Occasionally  some  destruction  of  the  red  blood  cells  is  caused  in 
animals  through  the  injection  of  carbolic  acid  directly  into  the  blood 
vessels,  and  in  one  case  of  poisoning  in  man  haemoglobin  was  detected 
in  the  urine,  indicating  that  some  of  the  red  cells  of  the  blood  had 
been  destroyed. 

Excretion.  —  Carbolic  acid  passes  through  the  tissues  unoxidized  for 
the  most  part,  but  a  certain  proportion  of  it  undergoes  a  partial  oxida- 
tion to  hydroquinone  and  pyrocatechin.  These  combine  in  the  body 
with  sulphuric  and  glycuronic  acids,  and  are  excreted  in  the  urine  as 
double  sulphates  (ether  sulphates)  and  glycuronates  of  phenol,  hydro- 
quinone and  pyrocatechin.  The  two  last-named  bodies  are  somewhat 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  397 

unstable,  and  tend  to  undergo  further  oxidation,  through  which  colored 
substances  are  formed.  When  carbolic  acid  has  been  absorbed,  there- 
fore, the  urine  tends  to  assume  a  dark,  dusky-green  color  which  may 
change  to  brown  or  even  black.  This  change  may  occur  in  the  body, 
and  the  urine  is  very  often  passed  of  a  greenish-brown  color,  but  further 
oxidation  takes  place  on  exposure  to  the  air,  resulting  in  deeper  colora- 
tion which  commences  at  the  surface  of  the  fluid  and  gradually  extends 
downwards.  The  depth  of  the  shade  depends  not  on  the  amount  of 
phenol  sulphate  in  the  urine,  but  on  that  of  the  dioxybenzols,  and  a 
darker  urine  is  often  observed,  therefore,  when  the  absorption  has  oc- 
curred from  an  open  wound  (in  which  the  conditions  are  especially 
favorable  to  oxidation)  than  from  much  larger  quantities  absorbed 
from  the  alimentary  canal. 

The  presence  of  glycuronates  in  the  urine  may  lead  to  its  reducing 
Fehling's  solution,  and  thus  give  rise  to  the  suspicion  of  glycosuria. 
On  the  other  hand,  the  passage  of  these  bodies  through  the  kidney 
often  causes  some  irritation  and  albumin uria.  The  double  sulphates 
of  the  urine  are,  of  course,  much  increased,  and  in  the  dog  the  whole 
of  the  ordinary  inorganic  sulphates  may  disappear,  the  urine  contain- 
ing only  double  sulphates. 

The  Chlorphenols,  in  which  chlorine  is  substituted  for  one  or  more  of  the 
hydrogen  atoms  of  carbolic  acid,  are  much  more  poisonous  to  microorgan- 
isms than  the  original  substance,  but  are  also  somewhat  more  poisonous  to 
mammals,  so  that  they  have  not  been  much  used.  A  similar  intensifying 
effect  is  seen  in  the  chlorine  substitution  products  of  the  narcotic  series,  e.  g. , 
chloroform.  The  most  poisonous  of  the  monochlor-phenols  is  parachlorphenol. 
Bromol  or  tribromphenol  has  been  used  to  a  limited  extent  in  therapeutics 
as  a  disinfectant  and  caustic. 

PREPARATIONS. 

ACIDTJM  CARBOLICUM  (B.  P.),  PHENOL  (U.  S.  P.),  carbolic  acid  or  phenol 
(C6H5OH)  forms  colorless,  deliquescent  crystals  when  recently  prepared,  but 
often  assumes  a  reddish  tinge  from  oxidation.  It  ha.s  a  characteristic  odor  and 
is  intensely  corrosive.  It  is  soluble  in  about  15  parts  of  water,  but  becomes 
liquid  when  10  parts  of  water  are  added  to  90  of  the  crystals,  forming  the 
Acidum  Carbolicum  Liquefactum  (B.  P.),  Phenol  Liquefactum  (U.  S.  P.).  This 
must  be  carefully  distinguished  from  the  ordinary  solution  of  carbolic  acid,  which 
contains  only  about  5  per  cent,  of  phenol,  while  the  liquefied  carbolic  acid  con- 
tains about  90  per  cent. 

Carbolic  acid,  0.03-0.2  G.  (J-3  grs.). 

Liquefied  carbolic  acid,  1-3  mins. 

Glyceritum  Phenolis(\J.  S.  P.),  Glycerinum  Acidi  Carbolici  (R.  P.),  20  per  cent, 
of  carbolic  acid  in  glycerin. 

Unguentum  Phenolis,  U.  S.  P.,  5  per  cent.;  Unguentum  Acidi  Carbolici,  B.  P., 
4  per  cent. 

Trochiscus  Acidi  Carbolici  (B.  P.),  each  containing  1  gr. 

Suppositoria  Acidi  Carbolici  (B.  P.),  each  containing  1  gr. 

Therapeutic  Uses.  —  Carbolic  acid  is  used  as  an  antiseptic  in  surgical 
operations  in  2-5  per  cent,  solution  in  water.  It  now  plays  a  muck 
less  important  role  in  surgery  than  it  did  in  the  first  days  of  anti- 
sepsis ;  in  fact,  in  many  clinics  in  which  it  was  once  the  only  anti- 
septic used,  and  in  which  it  was  applied  in  all  the  manifold  prepara- 


398  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

tions  then  known,  carbolic  acid  is  now  employed  only  to  preserve  the 
instruments  from  infection.  This  change  is  no  doubt  partially  due  to 
apprehension  of  its  irritant  action,  and  to  the  occasional  cases  of  pois- 
oning which  occurred  from  its  use,  but  chiefly  to  the  alterations  in 
surgical  technique  which  have  been  introduced  since  the  antiseptic 
method  was  first  invented.  The  tendency  now  is  to  reduce  the  use  of 
antiseptics  to  a  minimum  and  to  trust  instead  to  stricter  cleanliness 
and  asepsis.  Its  irritant  action  and  the  danger  of  absorption  have 
also  rendered  it  unpopular  as  a  dressing  or  lotion  after  operations  or 
injuries,  where  there  is  any  large  absorbent  surface,  or  where  irritation 
is  liable  to  be  injurious,  as  in  most  forms  of  skin  disease. 

It  is  still  used  as  a  disinfectant  in  septic  wounds,  though  greater 
reliance  is  now  placed  on  corrosive  sublimate  and  the  oxidizing  germi- 
cides, such  as  hydrogen  peroxide.  Strong  carbolic  acid  has  been 
applied  to  disinfect  wounds,  its  poisonous  effects  being  avoided  by  im- 
mediately washing  it  off  with  alcohol. 

Harrington  has  recently  drawn  attention  to  the  danger  of  applying 
dilute  solutions  in  bandages  to  injured  fingers  and  hands ;  he  found 
records  of  over  a  hundred  cases  in  which  this  had  led  to  gangrene 
necessitating  amputation. 

Carbolic  acid  has  also  been  employed  as  a  caustic,  the  liquefied 
preparation  being  preferred  for  this  purpose.  It  is  less  painful  than 
other  caustics  owing  to  its  anaesthetizing  action,  but  it  is  also  less 
efficient. 

Its  local  action  on  the  sensory  nerve  terminations  has  been  utilized 
in  itching  skin  diseases  and  it  may  be  noted  that  some  recent  local 
ansesthetics  are  benzol  derivatives  (see  page  314).  The  treatment 
of  deep-seated  abscesses  and  inflammation  by  the  local  injection  of 
carbolic  acid  solutions  has  passed  into  desuetude,  and  a  similar  fate 
has  befallen  its  use  to  limit  the  extension  of  erysipelas.  The  spray  of 
carbolic  acid  has  been  advised  in  laryngeal  and  pulmonary  disease,  but 
is  scarcely  met  with  in  recent  years.  A  solution  of  carbolic  acid  has 
been  employed  as  an  irritant  to  cause  inflammatory  reaction,  cicatricial 
adhesion  and  consequent  obliteration  of  small  cysts,  such  as  hydrocele, 
and  in  nsevus. 

Internally  carbolic  acid  was  tried  as  an  intestinal  disinfectant,  and 
in  many  infectious  fevers.  It  causes  marked  irritation  of  the  stomach, 
however,  and  probably  little  of  it  reaches  the  bowel,  as  it  is  rapidly 
absorbed,  and  other  less  irritant  and  less  soluble  bodies  have  therefore 
been  substituted  for  it.  Its  use  as  a  remedy  in  constitutional  diseases 
is  entirely  obsolete. 

It  may  be  prescribed  as  a  pill  or  in  capsules  for  internal  use,  as  the 
solutions  are  more  liable  to  cause  irritation ;  only  the  pure  acid  is 
prescribed  either  for  internal  or  external  application.  Crude  carbolic 
acid  may  be  employed  to  disinfect  stools,  latrines,  etc.,  and  is  quite 
unsuited  for  therapeutic  use.  The  ointment  is  comparatively  seldom 
prescribed,  as  it  is  found  more  irritant  than  many  other  equally  power- 
ful antiseptics.  The  glycerite  may  be  used  as  a  very  weak  caustic. 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  399 

Solutions  of  carbolic  acid  in  oil  have  little  or  no  antiseptic  action, 
because  they  fail  to  penetrate  into  the  microbes. 

Poisoning.  —  In  carbolic  acid  poisoning,  when  it  has  been  taken  by 
the  mouth,  the  first  treatment  is  the  removal  of  the  poison  by  the 
stomach  tube,  and  the  administration  of  demulcents  such  as  white  of 
egg ;  when  absorption  has  occurred  from  the  skin  or  from  a  wound, 
the  dressing  should  be  removed  at  once.  Lime  suspended  in  syrup 
has  been  recommended  in  cases  in  which  the  acid  has  been  swallowed, 
in  the  hope  that  an  insoluble  combination  may  be  formed  in  the  stom- 
ach. The  combination  of  phenol  with  sulphuric  acid  in  the  tissues 
forms  a  comparatively  harmless  body,  and  Baumann  and  Preusse  there- 
fore suggested  the  administration  of  sodium  sulphate  in  large  quanti- 
ties. It  is  found,  however,  that  this  is  of  little  or  no  use,  either  because 
the  tissues  in  which  the  synthesis  occurs  are  entirely  paralyzed  by  the 
excess  of  phenol,  or  more  probably  because  the  phenol  does  not  combine 
with  sulphates  as  such  in  the  body,  but  with  organic  sulphur  com- 
pounds which  are  only  in  process  of  being  oxidized  to  sulphuric  acid. 
When  coma  and  collapse  set  in,  the  patient  is  to  be  sustained  by  the 
application  of  warmth  externally,  and  by  the  administration  of  such 
central  nervous  stimulants  as  caffeine,  atropine,  or  camphor ;  artificial 
respiration  may  eventually  be  used,  although  there  is  little  prospect 
of  resuscitation  if  the  intoxication  has  advanced  so  far.  The  corrosion 
induced  by  carbolic  acid  locally  may  be  treated  by  washing  the  part 
with  alcohol,  which  dissolves  the  acid  readily.  Alcohol  has  also  been 
used  in  cases  in  which  the  poison  has  been  swallowed,  and  the  results 
are  said  to  have  been  satisfactory.  The  alcohol  only  serves  to  dilute 
the  poison  and  does  not  form  any  combination  with  it,  so  that  it  would 
seem  advisable  to  remove  the  mixture  by  the  stomach  tube. 

BIBLIOGRAPHY. 

Hmemann.    Deutsche  Klinik,  1870,  1871.    Arch.  f.  exp.  Path.  u.  Pharm.,  iv.,  p.  280. 

Gies.     Ibid.,  xii.,  p.  401. 

Baumann  and  his  pupils.  Pfliiger' s  Arch. ,  xiii. ,  p.  285.  Zts.  f.  phys.  Chem.,  i., 
p.  244  ;  ii.,  pp.  273,  350;  iii.,  pp.  156,  177.  Arch.  f.  Anat.  u.  Phys.,  1879,  p.  245. 

Bill     Amer.  Jour,  of  Med.  Sci.,  Ixiv.,  p.  17. 

Salkowsky.     Pfliiger' s  Arch.,  v.,  p.  335. 

Hoppe-Seylor.     Ibid.,  v.,  p.  470. 

Plugge.     Ibid.,  v.,  p.  538. 

Prudden.     Am.  Jour,  of  Med.  Sci.,  Ixxxi.,  p.  82. 

Tauber.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvi.,  p.  197. 

Schmiedeberg.     Ibid.,  xiv.,  p.  288. 

Turtschaninow.     Ibid.,  xxxiv.,  p.  208. 

Berkholz.     See  Unverrickt,  Centralb.  f.  inn.  Med.,  1895,  p.  4. 

Baglioni.  Arch.  f.  [Anat.  u.]  Phys.,  1900,  Supplem.,  p.  193.  Ztschr.  f.  allg.  Physiol., 
iii.,  p.  313. 

Minervini.     Arch.  f.  klin.  Chirurg.,  lx.,  p.  687. 

Harrington.     Am.  Jour,  of  Med.  Sci.,  cxx.,  p.  1. 

Cresol. 

The  three  cresols  are  nearly  related  to  carbolic  acid  chemically,  and  re- 
semble it  very  closely  in  their  effects.     Metacresol  is  less  poisonous  to  mam- 
mals and  less  irritant,  and  at  the  same  time  seems  to  be  more  destructive  tr 
microbes  than  carbolic  acid.     Orthocresol  is  more  dangerous  than  carboli 
acid,  and  paracresol  is  the  most  powerful  poison  of  all.     The  symptoi 


400  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

produced  by  these  bodies  are  identical  with  those  of  phenol.  They  are  ex- 
creted as  cresol  double  sulphates  mainly,  but  some  appears  in  the  urine  as 
the  sulphate  of  a  more  highly  oxidized  form,  dioxytoluol.  The  cresols  are 
constituents  of  the  tars  and  other  crude  antiseptic  substances.  They  are 
only  slightly  soluble  in  water,  and  there  has  been  some  difficulty  in  render- 
ing them  available  for  surgical  use,  but  this  has  been  overcome  by  forming 
emulsions  (creoliri),  or  by  dissolving  them  with  the  aid  of  salts  (solveol,  sol- 
utol)  or  suspending  them  by  means  of  soap  (lysol).  These  are  not  claimed 
to  be  pure  preparations  of  cresol,  but  the  three  isomeric  cresols  have  recently 
been  introduced  as  tricresol,  which  dissolves  in  water  to  the  extent  of  2  J  per 
cent.  These  preparations  are  not  devoid  of  poisonous  properties,  as  is  often 
stated  by  interested  individuals,  but  they  are  not  so  dangerous  as  carbolic 
acid.  They  are  used  chiefly  as  surgical  antiseptics,  but  creolin  has  also  been 
given  as  an  intestinal  disinfectant,  although  with  indifferent  results.  Their 
value  as  surgical  antiseptics  has  been  denied  by  some  writers  and  there  is  no 
question  that  it  has  been  much  overrated  by  others.  Kresamine  (ethylendi- 
amine  and  tricresol)  is  said  to  be  more  strongly  antiseptic  than  tricresol,  and 
has  been  recommended  in  diseases  of  the  skin  as  an  ointment  or  solution. 

Cresol  (U.  S.  P.),  a  mixture  of  the  three  cresols,  forms  a  colorless  or  straw- 
colored  fluid  with  a  phenol  odor.  Soluble  in  60  parts  of  water.  Dose,  0.05 
c.c.  (1  min.). 

Liquor  Cresolis  Compositus  (U.  S.  P.),  Cresol  50  percent,  suspended  in  water 
by  means  of  soap,  is  used  in  a  diluted  form  as  a  surgical  disinfectant. 

BIBLIOGRAPHY. 

Seybold.     Ztschr.  f.  Hygiene,  xxix.,  p.  377. 

Thymol. 

Another  phenol  homologue  is  thymol,  which  resembles  carbolic  acid 
closely  in  its  action,  though  it  causes  less  central  nervous  stimulation.  Con- 
vulsions and  tremors  are  rarely  induced  in  either  frogs  or  mammals,  and 
when  present,  are  very  much  less  intense  than  those  following  carbolic  acid. 
The  animal  generally  sinks  into  a  condition  of  apathy  and  weakness,  which 
gradually  passes  into  collapse  and  death.  Thymol  is  less  soluble  in  the 
fluids  of  the  body,  and  is  therefore  absorbed  more  slowly  than  carbolic  acid. 
It  is  also  less  irritant  to  wounded  surfaces  and  is,  according  to  most  observ- 
ers, considerably  more  poisonous  to  putrefactive  organisms,  while  less  pois- 
onous to  the  higher  animals.  In  poisoning  from  its  use,  fatty  degeneration 
of  the  liver,  marked  congestion  and  even  consolidation  of  the  lungs,  and  ir- 
ritation of  the  intestines  have  been  observed.  It  is  excreted  in  the  urine  in 
combination  with  sulphuric  and  glycuronic  acids,  partly  unchanged,  partly 
oxidized  to  thymolhydroquinone.  There  is  also  found  in  the  urine  a  green 
coloring  substance,  which  becomes  blue  on  the  addition  of  acid,  and  which 
seems  nearly  related  to,  but  not  identical  with  indigo.  Thymol  is  said  to 
be  more  liable  to  cause  renal  irritation  than  carbolic  acid  and  albumin  and 
even  blood  have  been  repeatedly  observed  in  the  urine  after  its  absorption. 

Thymol  (U.  S.  P.,  B.  P.)  (C6H3C3H7CH3OH)  occurs  in  common  thyme 
and  several  other  plants,  and  forms  large,  colorless  crystals,  which  have  the 
odor  of  thyme  and  are  very  insoluble  in  water.  0.03-2G.  (£-30  grs.)  in  pills, 
capsules,  emulsion,  or  in  solution  in  dilute  alcohol. 

Thymol  has  been  used  occasionally  as  an  antiseptic  lotion  in  ^  per  cent,  solu- 
tion and  as  a  mouth-wash  and  gargle,  for  which  carbolic  acid  is  rendered  un- 
suitable by  its  unpleasant  odor  and  its  corrosive  action.  As  an  internal 
remedy  it  has  proved  a  failure  in  the  treatment  of  various  constitutional  diseases, 
such  as  acute  rheumatism,  phthisis  and  typhoid  fever. 

It  has  recently  been  highly  recommended  as  an  anthelmintic  for  uncinaria  or 
anchylostoma  ;  it  is  given  in  capsules  or  emulsion  in  large  doses,  2  G.  (30  grs.), 
repeated  in  two  hours,  and  followed  in  six  or  eight  hours  by  a  brisk  saline  purge. 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  401 

BIBLIOGRAPHY. 

Husemann.     Arch.  f.  exp.  Path.  u.  Pharm.,  iv.,  p.  280. 

Blum.     Zts.  f.  physiol.  Chem.,  xvi.,  p.  514.     Deutsche  med.  Woch.,  1891,  p.  186. 

Leuin.     Virchow's  Arch.,  Ixv.,  p.  164. 

Baelz.     Arch,  der  Heilkunde,  xviii.,  p.  60. 

Kuessner.     Habilitationschr.,  Halle,  1878. 

Eucalyptol. 

Eucalyptol  (C10H18O)  is  the  chief  constituent  of  oil  of  eucalyptus,  which 
is  obtained  from  Eucalyptus  globulus  and  some  other  species.  It  is  also 
contained  in  the  oil  of  cajuput  and  in  other  volatile  oils.  It  has  been  re- 
commended as  a  surgical  antiseptic  and  in  the  same  class  of  internal  diseases 
as  thymol,  but  does  not  seem  to  have  any  special  virtues  distinguishing  it 
from  the  general  class  of  volatile  oils. 

Eucalyptol  (U.  S.  P.),  a  colorless  fluid,  having  a  characteristic,  camphor- 
aceous  odor  and  a  pungent,  spicy,  cooling  taste.  It  is  almost  insoluble  in 
water,  but  is  miscible  with  alcohol  in  all  proportions. 

Resorcin. 

The  three  dioxy benzols  —  resorcin,  pyrocatechin  and  hydroquinone  —  re- 
semble carbolic  acid  in  their  effects,  but  produce  a  more  intense  stimu- 
lation of  the  central  nervous  system,  for  convulsions  have  been  observed  in 
man  after  their  use.  This  is  especially  true  for  the  two  last,  resorcin  being 
much  less  toxic  than  these.  Resorcin  seems  to  be  equally  or  more  strongly 
antiseptic  than  phenol,  and  is  somewhat  less  poisonous,  while  the  others  are 
more  dangerous  ;  it  is  less  irritant  and  caustic  than  carbolic  acid.  All  three 
dioxybenzols  are  excreted  in  the  urine  in  combination  with  sulphuric  and 
glycuronic  acids.  They  are  in  part  subjected  to  further  oxidation,  leading  to 
coloration  of  the  urine  similar  to  that  seen  in  carbolic  acid  poisoning.  Pyro- 
catechin and  hydroquinone  when  added  to  blood  form  metha3moglobin  much 
more  readily  than  phenol,  and  also  tend  to  form  it  in  the  body  when  the 
intoxication  does  not  progress  too  rapidly  to  allow  of  this  alteration  in  the 
living  animal.  They  cause  a  much  greater  destruction  of  the  red  blood  cells 
than  phenol. 

Resorcinol  (U.  S.  P.),  resorcin,  metadioxybenzol  (C6H4(OH)2),  colorless, 
very  soluble  crystals,  with  a  faint  aromatic  odor.  0.3-0.6  G.  (5-10  grs.) ;  3 
G.  (45  grs.)  in  24  hours. 

Resorcin  is  a  remedy  which  has  fallen  into  almost  complete  disuse.  At 
first  introduced  as  an  antiseptic,  it  was  prescribed  for  a  short  time  as  an 
antipyretic,  but  has  proved  as  unsuitable  for  this  purpose  as  carbolic  acid  or 
aniline,  which  reduce  fever  temperature,  but  cause  symptoms  of  collapse  very 
readily.  It  has  been  used  as  an  intestinal  antiseptic  and  in  rheumatic  fever, 
but  has  here  again  been  supplanted  by  less  dangerous  remedies.  As  an  ex- 
ternal application,  it* has  been  applied  in  ointment  (5-10  per  cent.)  in  skin 
diseases,  and  has  been  injected  in  cystitis  and  gonorrhoea  in  solution  (1-3 
per  cent.)  but  in  both  cases  is  liable  to  produce  irritation  and  pain.  As  an 
internal  remedy  it  should  be  prescribed  in  dilute  solution  (1-2  per  cent.). 

BIBLIOGRAPHY. 

Andeer.     Centralbl.  f.  d.  med.  Wis.,  1881-1889. 
Baumann.     Zts.  f.  phys.  Chem.,  i.,  p.  244.     (See  Carbolic  Acid.) 
Brieger.     Zts.  f.  klin.  Med.,  iii.,  p.  25.     Arch.  f.  Anat.  u.  Phys.,  1879,  Suppl.,  p. 
61. 

Martin.     Therap.  Gaz.,  1887,  p.  289. 
Surbeck.    Deutsch.  Arch.  f.  klin.  Med.,  xxxii.,  p.  515. 
Danilewsky.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv.,  p.  105. 
26 


402  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

2.   Pyrogallol. 

Pyrogallol,  the  only  trioxybenzol  that  has  been  largely  used,  pro- 
duces nervous  symptoms  resembling  those  of  carbolic  acid,  when  given 
in  very  large  doses  to  animals,  In  the  cases  of  poisoning  which 
have  been  observed  in  man,  the  symptoms  closely  resembled  those 
caused  by  smaller  quantities  in  animals,  in  that  these  nervous  phenom- 
ena were  almost  entirely  absent,  and  the  poison  acted  not  so  much 
directly  on  the  central  nervous  system,  as  upon  the  blood  corpus- 
cles. Many  of  the  other  members  of  this  series  cause  some  destruc- 
tion of  the  red  cells,  but  none  of  them  approach  pyrogallol  in  the  inten- 
sity of  their  eifects.  The  red  blood  cells  become  shrunken  and  angular 
and  lose  most  of  their  haemoglobin,  which  escapes  into  the  plasma  and 
is  changed  into  methsemoglobin  ;  the  blood  therefore  assumes  a  brown- 
ish-red color,  which  may  be  detected  in  the  living  animal  by  the  dis- 
coloration of  the  skin  and  mucous  membranes.  If  the  intoxication  is 
not  too  acute,  icterus  follows,  and  haemoglobin  and  methsemoglobin  are 
excreted  in  the  urine.  In  the  blood,  fragments  of  red  cells  and 
"  shadows,"  or  red  cells  deprived  of  their  coloring  matter,  are  seen  in 
large  numbers,  and  the  spectrum  of  methsemoglobin  can  be  obtained 
easily.  The  kidneys  are  also  affected,  and  the  resulting  nephritis 
is  indicated  by  the  presence  in  the  urine  of  albumin,  epithelium, 
and  casts,  along  with  the  products  of  the  decomposition  of  the 
blood.  The  nephritis  may  lead  to  uraemic  convulsions,  which  are 
sometimes  accompanied  by  the  nervous  tremors  characteristic  of  this 
series,  and  also  by  dyspnoea  and  cyanosis  from  the  lack  of  haemoglo- 
bin in  the  blood.  The  formation  of  methaemoglobin  is  generally  be- 
lieved to  be  connected  with  the  well-known  reducing  properties  of  py- 
rogallol, but  whether  the  methaemoglobin  is  a  direct  result  of  the 
reduction  caused  in  the  haemoglobin,  or  whether  a  secondary  oxidation 
accompanies  this  action,  is  unknown.  Pyrogallol  is  excreted  in  part 
in  combination  with  sulphuric  acid  in  the  urine,  in  part  as  unknown 
oxidized  products,  which  give  the  urine  a  dark  brown  or  black  color, 
even  when  no  blood  pigments  are  contained  in  it.  In  fatal  poisoning 
death  seems  to  be  due  to  the  blood  changes,  and  the  consequent  ne- 
phritis and  jaundice,  rather  than  to  the  direct  effect  of  the  drug  on 
the  central  nervous  system.  It  has  been  stated  that  the  debris  of  the 
red  blood  cells  fails  to  pass  through  the  capillaries  and  thus  leads  to 
thrombosis,  but  this  has  been  denied  by  later  investigators. 

The  skin  is  dyed  brown  when  pyrogallol  is  applied  to  it,  from  the 
products  of  oxidation  formed. 

Pyrogallol  (U.  S.  P.),  pyrogallic  acid  (C6H?(OH)3),  light,  colorless  crystals 
or  laminae  when  freshly  prepared,  which  rapidly  assume  a  darker  color  on 
exposure  to  light  and  air.  It  is  very  soluble  in  water  and  reduces  the  salts 
of  the  heavy  metals  even  in  the  cold.  It  is  used  only  externally. 

Pyrogallol  is  used  in  the  treatment  of  several  forms  of  skin  disease, 
especially  in  psoriasis,  in  which  it  is  applied  in  ointment  (5-20  per 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  403 

cent.).  It  is  dangerous  to  apply  it  to  very  large  surfaces,  however, 
and  many  authorities  therefore  advise  the  use  of  chrysarobin  in  its 
stead.  Pyrogallol  ought  never  to  be  used  internally.  Its  curative 
action  in  skin  diseases  may  be  due  to  its  slight  irritant  and  antiseptic 
properties,  but  is  referred  by  some  to  its  reducing  action.  Gallaceto- 
phenone  (CH3 — CO  —  C6H2(OH)3)  has  been  recommended  as  a  substi- 
tute for  pyrogallol  in  skin  affections. 

BIBLIOGRAPHY. 

Wedl     Wiener  Sitzungsber.,  Ixiv.,  p.  405. 

Neisser.     Zts.  f.  klin.  Med.,  i.,  p.  88. 

Weyl  u.  Anrep.     Arch.  f.  Anat.  u.  Phys.,  1880,  p.  234. 

Rekowski.     Therap.  Monatsch.,  1891,  p.  487.     (Gallacetophenone. ) 

3.   Naphtalin  and  Naphtol  (Naphthol). 

Naphtalin  and  its  compounds  alpha-  and  beta-naphtol  differ  in  some 
respects  from  the  other  members  of  the  series.  They  are  all  insoluble 
in  water,  but  the  naphtols  are  dissolved  in  the  alkalies.  Some  ques- 
tion has  arisen  as  to  whether  Naphtalin  is  really  an  antiseptic  in  itself, 
or  whether  it  owes  its  activity  to  the  formation  of  the  more 
soluble  naphtols.  Animals  poisoned  with  it  do  not  exhibit  the  ordi- 
nary symptoms  of  poisoning  with  an  aromatic  body,  even  when  it  is 
administered  for  several  weeks,  but  suffer  from  diarrhoea  and  lose  flesh 
rapidly,  either  from  disturbance  of  the  alimentary  canal  or  from  renal 
disorder.  The  urine  soon  contains  albumin,  casts  and  epithelium,  and 
the  kidney  is  found  in  a  condition  of  parenchymatous  nephritis.  The 
changes  in  the  eye  caused  by  naphlalin  and  naphtol  have  excited  some 
interest.  The  retina  is  seen  with  the  ophthalmoscope  to  be  dotted 
over  with  numerous  bright  points,  or  sometimes  to  contain  large  yellow 
plaques,  and  after  large  doses  subretinal  effusion  has  been  observed. 
At  the  same  time,  atrophy  of  the  optic  nerve  may  occur,  and  bright 
points  are  seen  in  the  vitreous  humor  similar  to  those  in  the  retina. 
A  slight  cloudiness  appears  in  the  lens  and  increases  rapidly  until  it 
becomes  quite  opaque  and  resembles  an  ordinary  cataract  in  man.  This 
does  not  seem  to  be  secondary  to  the  retinal  changes,  but  is  the  result 
of  an  inflammatory  infiltration  beginning  in  the  ciliary  body  and  iris 
and  extending  into  the  lens  and  finally  into  the  posterior  surface  of  the 
cornea.  These  changes  in  the  eye  have  generally  been  observed  in 
animals  treated  with  large  doses  of  naphtaline  or  naphtol,  and  have  not 
occurred  in  such  intensity  in  man  ;  but  v.  d.  Hoeve  states  that  com- 
mencing retinal  degeneration  may  be  induced  in  man  by  the  use  of 
naphtol  internally  or  externally  and  cautions  against  its  prolonged  ad- 
ministration. 

Large  doses  of  the  Naphtols  induce  symptoms  similar  to  those  of 
carbolic  acid  poisoning,  except  that  in  the  dog  no  convulsions  have 
been  observed,  and  in  the  other  mammals  they  seem  less  pronounced. 
They  are  irritating  to  the  mucous  membranes  when  they  come  in  con- 


404  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

tact  with  them  in  solution  or  in  vapor ;  thus  they  cause  sneezing  and 
coughing  when  applied  to  the  respiratory  passages,  and  in  the  course 
of  excretion  induce  pain  in  the  bladder  and  urethra  with  strangury  and 
swelling  of  the  mucous  membrane.  Injected  subcutaneously  or  ab- 
sorbed from  the  alimentary  canal  in  animals,  they  induce  acute  nephritis 
with  the  appearance  of  albumin  and  haemoglobin  in  the  urine,  and 
some  nephritis  has  been  caused  in  man  from  their  external  application. 
They  seem  to  have  less  effect  on  the  circulation  and  respiration  than 
the  other  aromatic  antiseptics,  but  resemble  them  in  tending  to  destroy 
the  red  cells  of  the  blood.  Alpha-naphtol  has  been  found  to  be  more 
strongly  antiseptic  than  the  beta  compound,  and  may  be  more  poison- 
ous, as  is  generally  stated,  but  no  satisfactory  investigation  has  appeared 
regarding  this  point.  Beta-naphtol  is  several  times  as  strongly  ger- 
micidal  as  carbolic  acid,  and  is  the  form  used  in  therapeutics. 

Naphtalin  is  partly  oxidized  in  the  tissues  and  appears  in  the  urine 
as  alpha-  and  beta-naphtol  and  naphtoquinone,  all  in  combination  with 
glycuronic  and  sulphuric  acid.  The  naphtols  are  excreted  in  combi- 
nation with  glycuronic  acid  mainly.  These  bodies  and  their  oxidized 
products  give  the  urine  a  reddish-brown  tint,  which  may  become 
deeper  on  exposure  to  the  air,  but  in  some  cases  it  retains  its  ordinary 
color. 

PREPARATIONS. 

Naphthalenum  (U.  S.  P.),  naphtalin  or  naphtalene  (C10H8),  colorless,  insol- 
uble crystals  with  a  coal-tar  odor  and  a  hot,  aromatic  taste.  0.06-0.3  G. 
(1-5  grs.). 

BETANAPHTHOL  (U.  S.  P.),  NAPHTHOL  (B.  P.),  Beta-naphtol  (C10H7OH), 
white  or  yellowish-white,  insoluble  crystals  or  powder,  with  a  faint  phenol  odor 
and  a  hot  taste.  0. 2-0. 6  G.  (3-10  grs. ). 

Therapeutic  Uses.  — Naphtalin  and  naphtol  were  at  first  introduced 
as  external  applications  in  parasitic  skin  diseases  of  various  forms,  but 
have  been  more  extensively  prescribed  as  intestinal  disinfectants.  In 
some  disorders,  such  as  diarrhoea,  in  which  the  walls  of  the  intestine 
are  only  secondarily  affected  by  the  putrefaction  of  the  contents,  they 
have  proved  very  efficacious,  but  when  the  intestinal  walls  themselves 
are  the  seat  of  the  primary  disease,  as  in  typhoid  fever  and  dysentery, 
they  are  of  more  doubtful  value.  They  have  been  employed  as  an- 
thelmintics  to  a  limited  extent,  and  apparently  with  some  success, 
though  they  have  not  proved  so  reliable  as  some  of  the  older  drugs 
used  for  this  purpose.  Naphtol  is  more  largely  used  than  naphtalin  in 
internal  medication,  and  may  be  prescribed  as  a  powder  or  in  capsules. 
They  are  used  externally  as  ointments  (5-10  per  cent.).  Naphtalene 
and  naphtol  ought  to  be  avoided  in  irritation  of  the  kidneys,  bladder 
or  urethra. 

BIBLIOGRAPHY. 


Willenz.    Therap.  Monatsheft,  1888,  p.  20. 
Baatz.     Centralbl.  f.  inn.  Med.,  1894,  p.  857. 
Lesnik.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiv.,  p.  168. 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  405 

Magnus.     Therap.  Monats.,  1887,  p.  387. 

Klingmann.     Virchow's  Arch.,  cxlix.,  p.  12. 

Manca  and  Ovio.     Arch.  Ital.  de  Biologic,  xxxiv.,  p.  265. 

v.  d.  Hoeve.     Arch.  f.  Ophthalmol.,  liii.,  p.  74. 


4.   Tar. 

The  action  of  the  various  crude  preparations  of  the  antiseptic  series 
resembles  that  of  the  pure  principles  but  as  in  most  of  them  the  creo- 
sols,  guaiacols  and  other  less  poisonous  aromatic  compounds  are  present 
in  larger  quantity  than  the  phenols  and  dioxybenzols,  they  are  less 
poisonous  than  carbolic  acid  and  its  simpler  homologues.  At  the  same 
time  these  higher  combinations  do  not  seem  to  be  much  less  antiseptic 
than  the  simpler  benzol  derivatives,  so  that  several  of  the  crude  prepa- 
rations possess  considerable  value  in  surgery  and  medicine. 


PREPARATIONS. 

Fix  Liquida  (U.  S.  P.,  B.  P.),  tar,  is  obtained  from  the  wood  of  Pinus 
palustris  and  other  species  of  Pinus  by  destructive  distillation  and  contains 
a  very  large  number  of  aromatic  bodies  mixed  with  others  of  less  importance. 
Oleum  Picis  Liquids  (U.  S.  P.),  oil  of  tar,  is  a  volatile  oil  distilled  from 
tar,  and  is  similar  to  creosote,  except  that  it  consists  almost  entirely  of 
guaiacols  and  their  compounds.  0.05-0.3  c.c.  (1-5  mins.). 

Syrupus  Picis  Liquids  (U.  S.  P.),  syrup  of  tar,  4-12  c.c.  (1-3  fl.  drs.). 

Unguentum  Picis  Liquidse  (U.  S.  P.,  B.  P.). 

Pix  Carbonis  Pr separata  (B.  P.),  prepared  coal-tar. 

Liquor  Picis  Carbonis  (B.  P.),  a  solution  of  coal-tar  in  tincture  of  Quil- 
laia  bark. 

Oleum  Cadinum  (U.  S.  P.,  B.  P.),  oil  of  cade  or  empyreumatic  oil  of  juniper. 
Juniper  tar  oil  is  the  tar  distilled  from  the  juniper,  and  contains  dioxybenzol 
and  guaiacol  combinations.  It  is  less  strongly  disinfectant  than  the  other 
tars. 

Tar  is  a  valuable  disinfectant,  which  is  very  generally  available  and 
is  much  cheaper  than  the  purer  bodies  of  the  aromatic  series.  It  may 
be  used  for  the  disinfection  of  excrementa,  latrines,  etc.,  where  the  cost 
of  even  crude  carbolic  acid  would  be  prohibitive. 

Tar  has  also  been  used  with  considerable  success  as  an  antiseptic  in 
skin- diseases,  in  which  it  may  be  applied  either  alone  or  as  an  oint- 
ment. It  is  only  slightly  irritating  to  the  skin,  and  some  absorption 
occurs,  as  is  often  seen  by  the  dark  color  of  the  urine.  Internally  it 
has  been  used  occasionally  as  an  anthelmintic  and  intestinal  disinfec- 
tant, much  more  frequently  as  an  "  expectorant "  in  cough  mixtures. 
Whether  it  has  any  eifects  on  the  lungs  or  not  in  these  cases  may  be 
questioned.  It  is  generally  given  as  the  syrup,  sometimes  as  tar  water. 


BIBLIOGRAPHY. 

Nencki  u.  Sieber.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiii.,  p.  1. 
Strom.     Arch.  d.  Pharmacie,  ccxxxvii.,  p.  525. 


406  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Creosote. 

Creosote  may  be  regarded  as  a  wood-tar  from  which  the  more 
poisonous  phenols  and  the  less  volatile  bodies  have  been  eliminated, 
leaving  guaiacols  and  creosols  as  the  chief  constituents.  Its  action 
is  similar  to  that  of  carbolic  acid,  except  that  it  has  less  tendency  to 
induce  nervous  symptoms,  and  is  less  irritant  and  poisonous.  On  the 
other  hand,  it  seems  at  least  as  strongly  antiseptic  as  carbolic  acid,  and 
according  to  some  investigators,  far  excels  it  as  a  germicide. 

PREPARATIONS. 

Creosotum  (U.  S.  P.,  B.  P.)  is  obtained  from  wood-tar,  preferably  from 
beech  tar,  and  is  an  almost  colorless  oily  liquid  with  a  smoky  odor  and  hot, 
burning  acrid  taste.  It  is  slightly  soluble  in  water,  but  mixes  readily  with 
alcohol.  It  tends  to  darken  in  color  when  exposed  to  the  light.  0.05-0.3 
c.c.  (1-5  mins.). 

Aqua  Creosoti  (U.  S.  P.),  a  very  dilute  solution  of  creosote  in  water,  less 
than  one  per  cent.  2-8  c.c.  (J-2  fl.  drs.). 

Mistura  Creosoti  (B.  P.)  containing  spirits  of  juniper,  £-1  fl.  oz. 

Unguentum  Creosoti  (B.  P.). 

Creosote  may  be  administered  in  pills,  capsules,  in  solution  in  alcohol  or 
cod-liver  oil,  or  as  a  mixture  (B.  P.).  The  wine  of  creosote,  which  has  been 
a  popular  remedy,  contains  it  dissolved  in  wine  along  with  some  brandy 
and  tincture  of  gentian.  It  ought  not  be  allowed  to  reach  the  mucous 
membranes  in  a  concentrated  form,  as  it  is  liable  to  irritate  them. 

Therapeutic  Uses.  —  Creosote  is  comparatively  seldom  used  except 
in  the  treatment  of  pulmonary  phthisis  and  gangrene,  and  chronic 
bronchial  inflammation.  It  is  generally  given  by  the  mouth  in  these 
cases,  but  has  also  been  injected  hypodermically  or  into  the  rectum  ;  the 
vapor  is  recommended  as  an  inhalation,  and  some  practitioners  have 
injected  creosote  solution  into  the  trachea,  in  order  to  ensure  its  reach- 
ing the  lungs.  None  of  these  methods  are  believed  to  give  such  good 
results  as  the  ordinary  administration  by  the  mouth. 

The  results  of  creosote  medication  are  still  disputed.  Many  clin- 
icians state  that  a  general  improvement  follows  it  in  phthisical  pa= 
tients,  that  the  appetite  is  improved,  the  cough  and  expectoration  les- 
sened, and  that  the  patient  feels  stronger  and  better.  On  the  other 
hand,  others  are  extremely  sceptical  as  to  any  benefits  arising  from 
creosote,  and  regard  it  as  merely  one  of  the  countless  remedies  which 
have  been  recommended  in  this  condition,  and  which  after  a  shorter 
or  longer  period  of  popularity  have  passed  into  oblivion. 

It  is  generally  supposed  by  the  advocates  of  the  creosote  treatment 
that  the  remedy  destroys  the  tubercle  bacillus  in  the  lungs  through  its 
antiseptic  properties.  On  the  other  hand,  animals  infected  with  tubercle 
and  treated  with  creosote  die  as  soon  as  controls  which  are  untreated, 
and  the  sputum  of  phthisical  patients  treated  with  creosote  is  as  viru- 
lent as  that  of  others  not  so  treated.  Besides,  the  administration  of 
creosote  by  other  ways  than  by  the  mouth  is  said  to  be  very  much  less 
efficacious.  Another  explanation  of  the  creosote  action  is  that  it  acts 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  407 

as  an  intestinal  antiseptic  and  prevents  the  secondary  infection  of  the 
bowel ;  but  it  has  been  objected  to  this  that  the  other  intestinal  anti- 
septics are  of  little  value  in  tuberculosis.  It  seems  useless  to  specu- 
late on  the  method  of  action  until  it  has  been  definitely  determined 
that  creosote  is  of  value  in  phthisis,  and  this  can  be  done  only  by 
careful  statistical  inquiry.  The  medical  profession  seems  to  have  much 
less  faith  in  the  efficacy  of  the  creosote  treatment  than  it  had  a  few 
years  ago,  when  it  was  not  generally  recognized  that  pulmonary  tuber- 
culosis is  curable  by  hygienic  measures  in  a  considerable  proportion  of 
instances. 

Creosol,  an  ether  of  dioxytoluol,  is  contained  in  creosote  and  other  wood- 
tar,  and  has,  as  far  as  is  known,  effects  similar  to  those  of  the  allied  bodies, 
but  has  not  been  investigated  so  carefully  as  some  of  the  others. 

Guaiacol,  the  methyl  ether  of  pyrocatechin,  seems  to  be  somewhat  more 
poisonous  than  carbolic  acid  according  to  Marfori,  whose  preparations, 
however,  were  by  no  means  pure  ;  the  symptoms  induced  were  those  character- 
istic of  the  series.  It  is  excreted  in  the  urine  in  combination  with  sulphuric  and 
glycuronic  acids. 

Guaiacol  Carbonate  seems  to  have  the  same  effects  as  guaiacol,  into  which  it 
is  decomposed  in  the  intestine. 

It  was  found  a  few  years  ago  that  guaiacol  applied  to  the  skin  over  a  sufficiently 
wide  area  produced  a  marked  fall  of  temperature  in  fever,  but  this  does  not  seem 
to  be  any  specific  effect  of  guaiacol,  and  would  probably  have  resulted  from  the 
application  of  any  other  equally  volatile  member  of  the  group.  The  explanation 
is  that  a  certain  proportion  of  the  guaiacol  applied  is  absorbed  from  the  skin,  and 
the  fall  of  temperature  is  one  of  the  symptoms  of  poisoning.  Considerable 
quantities  of  guaiacol  have  been  recovered  from  the  urine  after  this  method  of 
medication.  The  fall  of  temperature  is  generally  abrupt  and  is  accompanied  by 
some  exhaustion  and  weakness,  and  by  profuse  perspiration.  The  temperature 
soon  rises  again  to  its  former  height  with  shivering  and  rigors,  and  there  seems 
good  reason,  therefore,  why  guaiacol  should  not  be  classed  iimong  the  more  satis- 
factory antipyretics. 

Guaiacol  (U.  S.  P.),  (C6H4- OH- OCH3),  colorless  crystals,  or  fluid  with  an 
agreeable  aromatic  odor,  soluble  in  53  parts  of  water  and  in  alcohol.  Dose, 
0.5  c.c.  (8  mins.). 

Guaiacol  has  been  administered  as  a  substitute  for  creosote  in  tubercular 
disease.  It  is  generally  given  in  solution  in  alcohol  or  cod-liver  oil,  or  in  pills. 
It  has  been  injected  hypodermically. 

Guaiacolis  Carbonas  (U.  S.  P.)  ((C7H7O)2CO3),  an  almost  tasteless  powder,  is 
given  in  cachets  in  doses  of  0.2-0.5  G.  (3-8  grs. )  in  pulmonary  phthisis. 

Ichthyol. 

Ichthyol,  thiol,  and  similar  bodies  possess  some  antiseptic  action,  although 
they  are  believed  to  be  less  powerful  than  carbolic  acid.  Applied  to  the  skin, 
ichthyol  causes  slight  irritation,  which  is  apparently  of  benefit  in  some  cu- 
taneous diseases,  and  it  has  therefore  been  used  extensively  for  this  action. 
It  is  said  to  cause  marked  contraction  of  the  vessels  when  it  is  applied 
locally,  but  this  requires  confirmation.  A  certain  amount  of  absorption  oc- 
curs when  it  is  rubbed  into  the  skin,  for  the  sulphur  of  the  urine  has  been 
found  to  be  augmented.  Taken  internally  in  large  quantities,  it  acts  as  a 
gastric  and  intestinal  irritant  and  produces  diarrhoea,  but  it  is  only  very 
feebly  poisonous.  It  has  been  said  to  lessen  to  a  marked  extent  the  nitro- 
genous metabolism,  but  this  seems  incorrect,  for  Helmers  found  only  a  very 


408  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

slight  and  inconstant  fall  in  the  nitrogen  of  the  urine  in  man.     It  is  ex- 
creted in  the  urine  and  probably  by  the  intestinal  wall. 

Ichthyol  has  been  strongly  recommended  in  the  treatment  of  a  number  of 
skin  diseases,  including  erysipelas.  It  is  generally  used  as  an  ointment  con- 
taining equal  parts  of  ichthyol  and  of  vaseline,  but  may  be  used  in  ten 
per  cent,  or  even  weaker  dilution.  It  has  also  been  advised  as  an  applica- 
tion over  inflamed  and  rheumatic  joints,  indurated  glands  and  swellings,  and 
chronic  inflammations  of  the  pelvic  viscera,  and  is  said  to  cause  the  absorp- 
tion of  the  products  of  inflammation.  Its  effects  can  be  explained  in 
these  cases  only  by  the  slight  irritant  action  on  the  skin.  It  has  been 
given  internally  in  pills  or  capsules  in  doses  of  0.2-0.5  G.  (3-8  grs.)  in  cases 
of  rheumatism,  erysipelas,  and  in  many  chronic  diseases,  but  seems  of  very 
doubtful  benefit.  In  fact,  ichthyol  has  in  the  last  few  years  been  enthusiastically 
praised  as  a  remedy  in  the  most  diverse  conditions,  and  it  seems  probable  that  its 
sphere  of  utility  will  be  very  much  more  restricted  in  the  future,  if  it  does  not 
disappear  from  therapeutics  entirely. 

BIBLIOGRAPHY. 

R.  Abel     Centralbl.  f.  Bacteriologie,  xiv.,  p.  413. 
Zuelzer.     Monatsh.  f.  prakt.  Dermatologie,  1886,  p.  547. 
Helmers.     Virchow's  Arch.,  cxxxv.,  p.  135. 

5.    Salicylic  Acid. 

Salicylic  acid  differs  from  phenol  chiefly  in  being  very  much  less 
poisonous  to  the  higher  animals,  while  it  is  practically  of  equal  an- 
tiseptic value,  provided  the  conditions  are  favorable.  The  salicylates 
produce  the  same  effects  as  the  free  acid,  excepting  that  they  are 
much  less  irritant  to  the  skin  and  mucous  membranes.  It  was  for- 
merly stated  that  the  salicylate  of  soda,  which  is  the  only  salt  that  has 
been  largely  used,  was  devoid  of  antiseptic  action,  but  this  has  been 
shown  to  be  incorrect. 

Antiseptic  Action.  —  Salicylic  acid  retards  the  digestion  of  proteids 
by  the  gastric  and  pancreatic  juices,  and  the  decomposition  of  gluco- 
sides  by  the  unorganized  ferments,  but  how  far  this  effect  is  due  to  the 
free  acid,  and  how  far  to  a  specific  antiferment-action,  cannot  be  defi- 
nitely stated.  The  putrefaction  of  proteid  solutions,  and  the  alcoholic 
and  acetic  acid  fermentations  are  also  retarded,  or  entirely  prevented 
by  the  presence  of  comparatively  small  quantities  of  salicylic  acid  or  of 
the  salicylates.  They  offer  some  points  of  contrast  with  carbolic  acid, 
however,  for  it  is  found  that  if  much  proteid  be  present  the  salicylic 
preparations  are  generally  less  efficient  than  phenol ;  this  is  perhaps 
due  to  the  phenol  being  volatile  and  therefore  penetrating  more  readily 
and  forming  less  stable  combinations  with  the  proteid.  Salicylic  acid 
on  the  other  hand  does  not  evaporate,  and  therefore  preserves  bodies 
which  are  exposed  to  the  air  for  a  longer  time  than  carbolic  acid, 
which  is  soon  dissipated.  These  considerations  may  perhaps  explain 
the  very  different  results  which  have  been  obtained  by  different  ob- 
servers in  regard  to  the  comparative  germicidal  power  of  these  sub- 
stances. The  movements  of  plant  protoplasm,  protozoa  and  leucocytes 
are  prevented  by  salicylic  acid  as  by  quinine  and  the  other  aromatic 
antiseptics. 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  409 

Irritant  Action.  —  Salicylic  acid  is  much  less  irritant  than  phenol, 
but  when  it  is  applied  for  some  time  as  a  powder  to  wounds,  mucous 
membranes,  or  even  the  skin,  it  may  induce  the  same  corrosion  and 
necrosis  as  have  been .  mentioned  under  carbolic  acid.  In  solution  it 
has  a  destructive  action  on  the  horny  layer  of  the  epidermis,  which  be- 
comes softened  and  easily  removed,  without  any  noticeable  irritation 
having  been  induced.  It  sometimes  causes  soreness  and  irritation  of 
the  mouth  and  throat  when  swallowed  in  powder,  and  congestion  and 
even  erosion  of  the  mucous  membrane  of  the  stomach  have  been  ob- 
served. In  dilute  solution,  however,  the  acid  has  no  such  effect,  and 
even  comparatively  concentrated  solutions  of  the  salts  seem  almost 
devoid  of  corrosive  properties. 

Symptoms.  —  Salicylic  acid  and  its  salts  are  rapidly  absorbed  from 
the  stomach  and  intestine,  and  as  a  general  rule  produce  no  symptoms, 
unless  when  given  in  very  large  doses.  Some  individuals,  however, 
are  peculiarly  sensitive  to  the  action  of  salicylic  acid,  and  in  these, 
comparatively  small  doses  are  followed  by  symptoms  which  are  gen- 
erally of  only  slight  importance,  but  which  are  sometimes  sufficiently 
grave  to  cause  anxiety,  and  in  very  rare  cases,  have  been  followed  by 
death. 

The  ordinary  symptoms  are  a  feeling  of  heaviness  and  fulness  in  the 
head,  with  hissing  or  roaring  sounds  in  the  ears  exactly  resembling 
those  produced  by  quinine.  These  may  be  followed  by  some  confusion 
and  dulness,  and  by  indistinct  sight  and  hearing.  Very  often  the 
patient  complains  of  excessive  perspiration  and  a  sense  of  warmth  all 
over  the  body.  Dyspnoea,  marked  by  exceedingly  deep  and  labored 
respiration,  has  been  noted  in  more  serious  cases  of  poisoning,  and  a 
condition  of  collapse  with  slow  weak  pulse,  subnormal  temperature, 
and  partial  or  complete  unconsciousness  may  follow.  In  others,  de- 
lirium and  hallucinations  of  sight  and  hearing  have  occurred,  these 
being  more  frequently  seen  in  chronic  alcoholic  patients  .and  in  cases 
of  diabetes  than  under  other  conditions.  Albumin,  casts,  and  even 
haemoglobin  and  blood  in  the  urine  have  been  noted  as  sequelae.  Vari- 
ous forms  of  skin  eruptions  have  been  described  as  occurring  under  the 
use  of  salicylic  acid,  sometimes  after  a  single  dose,  but  much  more 
frequently  after  prolonged  treatment.  They  resemble  those  seen  under 
the  antipyretics,  but  seem  to  be  less  frequently  elicited  by  salicylic 
acid.  Abortion  has  been  repeatedly  observed  under  salicylate  treat- 
ment, but,  as  in  the  case  of  quinine,  it  seems  open  to  question  whether 
this  was  due  to  the  remedy  or  to  the  disease.  Haemorrhages  from  the 
uterus,  nose,  mouth  and  intestine  have  also  been  credited  to  the  action 
of  this  drug,  and,  in  fact,  nose-bleeding  has  been  said  to  occur  in  a 
considerable  proportion  of  the  cases  treated  with  it.  Numerous  other 
symptoms  have  been  noted  after  salicylic  acid,  but  so  rarely  that  a 
doubt  may  be  entertained  as  to  whether  they  were  not  due  to  some 
special  condition,  or  perhaps  to  some  impurity  in  the  drug. 

In  animals,  salicylic  acid  injected  intravenously  causes  some  acceler- 
ation of  the  pulse  and  respiration,  followed  by  slowness  and  weakness 


410  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

of  the  heart,  and  often  by  marked  dyspnoea.  Depression  of  the  central 
nervous  system  is  shown  by  slowness,  weakness  and  incoordination  of 
the  spontaneous  movements,  and  eventually  by  stupor  and  arrest  of 
the  respiration,  which  is  generally  preceded  by  convulsions.  Photo- 
phobia and  clonic  spasms  have  been  observed  in  some  dogs.  Hyper- 
semia  of  the  kidney,  liver,  brain  and  tympanum  are  sometimes  found  at 
the  autopsy  on  dogs  poisoned  with  salicylic  acid,  and  when  the  drug 
has  been  given  in  powder,  congestion,  irritation  and  necrosis  of  the 
gastric  mucous  membrane.  This  irritation  of  the  stomach  often 
causes  vomiting  in  dogs,  and  the  poison  being  thus  eliminated,  no 
further  symptoms  appear. 

In  the  frog,  salicylic  acid  produces  quickened  respiration  and  in- 
creased reflexes,  followed  by  depression  of  the  spontaneous  movements, 
tremor  and  clonic  contractions.  The  heart  is  slow,  dilated  and  weak. 

The  symptoms  elicited  by  salicylic  acid  and  its  salts  are  therefore 
verv  indefinite,  and  with  few  exceptions  occur  so  seldom  in  man  that 
they  may  be  discussed  very  shortly. 

The  Disorders  of  Hearing  have  been  ascribed  to  congestion  of  the 
tympanum,  but  may  perhaps  indicate  some  changes  in  the  nerve  cells 
of  the  ear  analogous  to  those  observed  under  quinine.  As  a  general 
rule  they  pass  off  in  the  course  of  a  few  hours  or  days,  but  they  some- 
times leave  a  more  or  less  permanent  impairment  of  the  sense  of  hear- 
ing. The  Dimness  of  Sight,  sometimes  amounting  to  complete  blind- 
ness, is  due  to  vascular  or  retinal  changes  in  the  eye  (see  Quinine),  and 
some  disturbance  of  the  circulation  of  the  brain  and  head  may  be  the 
cause  of  the  dulness  and  fulness  of  the  head  complained  of,  and  of  the 
not  infrequent  epistaxis.  Maragliano  showed  by  plethysmographic 
measurements  that  the  Vessels  of  the  Skin  are  dilated  by  salicylic  acid 
in  the  same  way  as  by  the  antipyretics.  The  exact  mechanism  by 
which  these  alterations  in  the  distribution  of  the  blood  are  produced  is 
unknown,  but  the  most  probable  explanation  would  seem  to  be  that 
the  vaso-dilator  centres  in  the  medulla  controlling  these  areas  are  excited. 

The  general  Blood-Pressure  is  found  to  be  increased  by  small  quan- 
tities of  the  salicylates  from  stimulation  of  the  vaso-con stricter  centre, 
while  after  very  large  injections  into  the  blood  vessels,  the  pressure  is 
lowered,  partly  perhaps  from  depression  of  the  centre,  but  mainly  from 
the  cardiac  action  of  the  drug. 

Small  quantities  are  found  to  accelerate  the  Heart  in  animals  in  the 
same  way  as  small  doses  of  the  other  aromatic  bodies,  apparently  from 
direct  action  on  the  cardiac  muscle.  Very  large  doses  produce  a  slow, 
weak,  and  dilated  heart,  and  a  corresponding  fall  in  the  blood-pressure. 

The  acceleration  of  the  Respiration  and  the  dyspnoea,  which  have 
been  noted  occasionally  in  man,  seem  to  be  due  to  some  central  action. 
In  animals  the  respiration  is  first  accelerated  to  some  extent,  and  then 
slowed,  and  some  observers  have  attributed  the  acceleration  to  irrita- 
tion of  the  endings  of  the  pneumogastric  nerves  in  the  lungs,  without, 
however,  bringing  forward  any  satisfactory  evidence  in  support  of  this 
explanation.  It  is  more  probable  that  the  respiratory  centre  is  first 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  411 

excited  and  then  depressed,  and  eventually  paralyzed  by  very  large 
quantities  of  the  drug.  Death  seems  to  be  due  to  this  paralysis,  the 
heart  continuing  to  beat  for  some  time  afterwards. 

The  effects  of  salicylic  acid  on  the  Central  Nervous  System  seem  to 
be  comparatively  slight,  except  in  cases  in  which  a  special  idiosyncrasy 
exists.  No  such  convulsive  action  as  occurs  under  others  of  the  aro- 
matic series  has  been  observed  under  it,  and  in  animals  there  seems  no 
marked  depression  save  in  the  medulla  oblongata.  The  convulsions 
which  are  observed  before  death,  are  probably  not  due  to  the  direct 
action  of  the  drug,  but  to  the  asphyxia.  In  the  medulla  oblongata  the 
respiratory  and  vaso-constrictor  centres,  and  probably  the  vaso-dilator, 
seem  to  be  first  stimulated  and  then  depressed.  In  the  frog  depres- 
sion and  paralysis  of  the  spinal  cord  are  produced  by  large  doses. 

The  Perspiration  which  so  often  follows  the  administration  of  sali- 
cylic preparations,  may  be  due  in  part  to  the  dilation  of  the  skin  ves- 
sels, but  is  probably  to  be  ascribed  rather  to  increased  activity  of  the 
sweat  centres.  Some  of  the  Skin  Rashes  may  also  be  caused  by  the 
dilation  of  the  cutaneous  vessels,  and  perhaps  in  all  cases  this  may  be 
looked  upon  as  a  favorable  condition,  which  leads  to  eruptions  in  indi- 
viduals who  are  predisposed  to  them. 

The  peripheral  Muscles  and  Nerves  do  not  seem  to  be  more  affected 
by  salicylic  acid  than  by  the  other  members  of  the  series. 

Salicylic  acid  and  its  salts  increase  to  some  extent  the  Secretion  of 
the  Urine,  probably  through  a  direct  action  on  the  renal  epithelium, 
although  the  increased  formation  of  urea  may  also  play  a  part  in  the 
slight  diuresis.  Irritation  of  the  kidney  and  nephritis  are  observed 
in  some  cases,  with  the  appearance  of  albumin  and  blood  in  the  urine. 

The  salicylic  preparations  produce  a  slightly  augmented  flow  of 
Bile,  apparently  from  some  specific  action  on  the  liver  cells.  The 
increase  is  so  small,  however,  that  some  doubt  is  expressed  by  most 
writers  on  the  subject.  Pfaff  found  that  in  one  case  of  biliary  fistula 
in  man  the  concentration  of  the  bile  was  also  increased,  the  solids 
being  augmented  in  greater  proportion  than  the  fluid. 

Salicylates  have  been  said  to  lower  the  normal  Temperature,  but 
this  seems  to  be  erroneous,  except  when  very  large  quantities  produce 
a  condition  akin  to  collapse.  Some  of  the  results  may  also  be  due  to 
the  use  of  impure  preparations.  In  fever  patients,  however,  it  often 
causes  a  marked  fall  of  temperature,  and  it  was  formerly  used  as  an 
antipyretic  for  this  reason.  The  action  is  probably  explained  by  the 
dilation  of  the  cutaneous  vessels  and  the  increase  in  the  output  of  heat. 
(See  Antipyretics.)  Dilation  of  the  skin  vessels  also  occurs  in  normal 
persons  after  salicylates,  but  this  is  probably  counterbalanced  in  them 
by  increased  heat  formation.  The  fall  in  temperature  after  salicylic 
acid  is  generally  less  in  extent  and  of  shorter  duration,  than  that  fol- 
lowing the  members  of  the  antipyrine  series.  . 

In  its  passage  through  the  tissues,  salicylic  acid  modifies  the  Meta- 
bolism, as  is  shown  by  an  increase  of  10—12  per  cent,  in  the  nitrogen 
and  sulphur  of  the  urine.  This  indicates  a  considerably  augmented 


412  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION, 

decomposition  of  the  proteids  of  the  body,  but  whether  it  is  accom- 
panied by  increased  oxidation  is  unknown.  A  still  more  notable 
augmentation  of  the  uric  acid  excreted  has  been  observed,  different 
authors  estimating  it  at  30—45  and  even  100  per  cent.  The  number 
of  leucocytes  in  the  blood  has  been  found  to  undergo  a  corresponding 
increase. 

The  form  in  which  salicylic  acid  circulates  in  the  blood  was  for- 
merly the  subject  of  some  discussion,  owing  to  the  erroneous  belief  that 
its  salts  were  devoid  of  antiseptic  action.  It  is  now  known  to  exist 
in  the  blood  as  the  salicylates  of  the  alkalies.  Gaglio  states  that  it  is 
taken  up  from  the  blood  by  the  synovial  membranes  and  rapidly  ex- 
creted into  the  cavities  of  the  joints,  and  is  thus  capable  of  exercising 
a  specific  action  in  acute  rheumatism.  It  is  Excreted  by  the  kidneys, 
for  the  most  part  in  a  combination  with  glycocoll,  which  is  known  as 
salicyluric  acid,  and  which  is  strictly  analogous  to  hippuric  acid. 
Some  of  the  salicylic  acid  is  excreted  uncombined.  It  has  also  been 
found  in  the  milk,  perspiration  and  bile,  but  does  not  appear  to  be  ex- 
creted into  the  stomach. 

Several  compounds  which  owe  their  virtues  to  the  salicylic  acid 
radicle  are  used  in  medicine,  and  all  produce  similar  results  after  ab- 
sorption, but  vary  in  their  local  action.  Methyl  Salicylic  Ester,  which 
occurs  in  many  plants  and  forms  some  90  per  cent,  of  the  oil  of  winter- 
green,  and  almost  the  whole  of  the  volatile  oil  of  birch,  has  a  hot, 
burning  taste,  and  like  other  volatile  oils  produces  a  feeling  of  warmth 
in  the  stomach.  In  many  cases  it  is  well  borne,  but  some  patients 
complain  of  pain  in  the  stomach,  loss  of  appetite  and  even  nausea  and 
vomiting.  It  is  rapidly  absorbed  and  produces  the  characteristic 
symptoms  of  salicylic  acid  in  large  doses,  roaring  sounds  in  the  ears 
and  more  or  less  deafness.  It  is  partly  excreted  as  salicyluric  acid, 
the  decomposition  probably  occurring  mainly  in  the  intestine. 

Salol,  the  phenyl  salicylic  ester,  is  a  very  insoluble,  crystalline  body, 
which  has  little  or  no  local  action  in  the  mouth  or  stomach,  but  is  de- 
composed in  the  intestine  by  the  fat-splitting  ferment  of  the  pancreatic 
juice.  Some  decomposition  also  appears  to  occur  in  the  stomach,  at 
any  rate  under  certain  conditions.  The  products  of  its  decomposition, 
salicylic  and  carbolic  acids,  are  absorbed  and  produce  their  usual 
effects.  Salol  is  used  chiefly  as  a  substitute  for  salicylic  acid,  but  the 
formation  of  phenol  from  it  in  the  body  must  not  be  overlooked,  for  in 
several  cases  of  dangerous  poisoning  which  have  been  observed  under 
it,  the  symptoms  were  those  characteristic  of  carbolic  acid,  and  the  urine 
became  dark  in  color  from  the  phenol  oxidation  products.  In  moderate 
quantities,  salol  produces  the  disturbances  of  hearing  observed  under 
salicylic  acid,  without  any  symptoms  of  carbolic  poisoning. 

Other  salicylic  acid  compounds,  similar  to  salol,  are  betol  or  naphtalol 
(the  beta-naphtol  salicylate),  cresalol  (cresol  and  salicylic  acid),  thymo- 
salol  (from  thymol),  guaiacohalol,  while  saliphen,  malakine,  etc.,  have 
been  mentioned  among  the  antipyretics.  They  are  less  poisonous  than 
salol,  and  may  be  used  for  most  purposes  as  substitutes  for  salicylic 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  413 

acid.  Saliphen,  malakine  and  their  allies  have  a  more  powerful  anti- 
pyretic action  than  salicylic  acid.  On  the  other  hand,  the  salicylic 
esters,  including  methyl  and  phenyl  salicylates,  are  less  antiseptic  than 
salicylic  acid  and  its  salts. 

Salicin,  a  glucoside  found  in  many  species  of  willow  and  poplar,  is 
decomposed  into  salicylic  alcohol,  which  is  oxidized  to  salicylic  acid  in 
the  body,  so  that  its  action  after  absorption  is  similar  to  that  of  the 
acid.  It  is  unknown  whether  the  decomposition  occurs  in  the  alimen- 
tary canal  or  in  the  tissues,  but  from  the  fact  that  it  is  excreted  mainly 
as  salicin  when  it  is  injected  intravenously,  it  would  seem  probable 
that  the  decomposition,  like  that  of  the  ordinary  esters,  takes  place 
chiefly  in  the  intestine.  It  is  very  bitter,  but  does  not  irritate  the 
mucous  membranes,  and  is  not  so  certain  in  its  action  as  salicylic  acid 
and  some  of  its  esters.  When  administered  by  the  mouth  it  is  excreted 
in  the  urine  partly  as  salicin,  partly  as  saligenin  or  salicyl  alcohol,  and 
partly  as  salicylic  and  salicyluric  acids. 

PREPARATIONS. 

ACIDUM  SALICYLICUM  (U.  S.  P.,  B.  P.),  salicylic  acid  (CfiH4OHCOOH) 
small,  white,  needle-like  crystals,  or  a  light  crystalline  powder,  odorless  with 
a  sweetish,  afterwards  acrid,  burning  taste,  slightly  soluble  in  water,  very 
soluble  in  alcohol  or  ether.  A  reddish  tinge  indicates  the  presence  of  car- 
bolic acid  or  other  impurities,  and  salicylic  acid  for  internal  use  ought  to  be 
entirely  colorless.1  Salicylic  acid  is  much  more  soluble  in  solutions  of  neu- 
tral salts,  such  as  the  borates  or  citrates,  than  in  pure  water.  0.3-2  G.  (5-80 
grs.).  It  is  generally  given  in  capsules  or  tablets. 

Unguentum  Acidi  Salicylici  (B.  P.),  2  per  cent. 

SODII  SALICYLAS  (U.  S.  P.,  B.  P.),  sodium  salicylate  (C6H4OHCOONa),  a 
white  odorless  powder  with  a  sweetish  taste,  very  soluble  in  water,  less  so 
in  alcohol.  0.6-2  G.  (10-30  grs.)  in  capsules  or  tablets,  or  dissolved  in 
syrup. 

Lithii  Salicylas  (U.  S.  P.),  0.3-2  G.  (5-30  grs.). 

Ammonii  Salicylas  (U.  S.  P.),  0.25  G.  (4  grs.). 

Strontii  Salicylas  (U.  S.  P.),  1.0  G.  (15  grs.). 

Oleum  Gaultherice,  (U.  S.  P.),  oil  of  wintergreen,  a  colorless  or  yellowish  fluid 
with  a  characteristic,  pleasant  odor  and  a  sweetish,  aromatic  taste,  insoluble  in 
water,  soluble  in  alcohol,  contains  90  per  cent,  of  methyl  salicylate.  0.3-1  c.c. 
(5-15  mins. )  in  emulsion  or  capsules. 

Oleum  Betulce  (U.  S.  P.),  oil  of  sweet  birch. 

Methylis  Salicylas  (U.  S.  P.),  artificial  oil  of  wintergreen  (C6H4OHCOOCH3), 
is  practically  identical  with  the  oil  of  sweet  birch  and  forms  90  per  cent,  of 
the  oil  of  wintergreen.  It  may  be  prescribed  in  the  same  doses  and  forms 
as  the  latter. 

Spiritus  Gauftherise  (IT.  S.  P.)  is  used  as  a  flavor  chiefly.     1  c.c.  (15  mins.). 

Salicinum  (U.  S.  P.,  B.  P.),  salicin  (C6HnO5OC6H4CH2OH),  a  glucoside 
obtained  from  several  species  of  willow  and  poplar,  consists  of  white,  silky, 
crystalline  needles,  with  a  very  bitter  taste,  soluble  in  28  parts  of  water.  It 
is  decomposed  by  ferments  into  glucose  and  saligenin  or  salicyl  alcohol 
(C6H4OHCH2OH).  0.5-2  G.  (8-30  grs.)  or  more  every  3  or  4  hours,  given 
in  powder,  capsules  or  in  solution,  which,  however,  is  very  bitter. 

1  Salicylic  acid  formed  synthetically  from  phenol  is  often  said  to  be  more  poisonous 
than  that  obtained  from  the  oil  of  wintergreen  (methyl  salicylate),  but  this  is  due  not 
to  any  difference  in  the  acid,  but  to  the  presence  of  carbolic  acid  and  other  impurities 
in  the  artificial  preparation. 


414  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

SALOL  (B.  P.),  PHENYLIS  SALICYLAS  (U.  S.  P.),  phenyl  salicylate  (C6H4- 
OHCOOC6H5),  a  white  crystalline  powder,  odorless  or  faintly  aromatic,  almost 
tasteless,  almost  insoluble  in  water,  decomposed  by  the  pancreatic  juice  into 
salicylic  acid  and  phenol.  0.5-2  G.  (5-30  grs.)  in  powder  or  capsule. 

Aspirin  or  acetylsalicylic  acid,  is  very  slightly  soluble  in  water  and  has  a 
more  pleasant  acid  taste  than  salicylic  acid  but  offers  no  further  advantages 
over  it.  It  is  decomposed  into  salicylic  acid  in  the  intestine.  Dose,  2-3 
G.  (30-40  grs.). 

Therapeutic  Uses,  —  Salicylic  acid  and  the  salicylate  of  soda  were  at 
one  time  used  to  a  considerable  extent  as  antiseptics  in  surgery,  and  in- 
deed promised  to  supplant  carbolic  acid  for  this  purpose,  as  they  were 
less  irritating  and  also  less  poisonous.  They  have  been  less  used  of 
late  years,  and  although  bacteriological  experiment  has  shown  that  the 
acid  is  at  least  as  destructive  to  the  pyogenic  organisms  as  carbolic 
acid,  most  surgeons  find  it  less  satisfactory  in  practice.1 

Salicylic  acid  is  occasionally  applied  locally  in  excessive  sweating, 
and  has  also  been  used  in  various  skin  affections  in  which  it  is  desir- 
able to  soften  or  partially  dissolve  the  epidermis.  Both  acids  and  salts 
are  absorbed  too  rapidly  to  act  as  intestinal  disinfectants. 

In  1875  it  was  found  to  have  antipyretic  properties,  and  for  a  few 
years  it  was  used  as  a  general  antipyretic  in  fever,  but  has  been  entirely 
supplanted  for  this  purpose  by  the  more  recently  discovered  antipyrine 
series.  It  was  also  suggested  as  a  substitute  for  quinine,  but  has  no 
such  specific  action  on  the  malarial  organisms. 

The  chief  sphere  of  usefulness  of  salicylic  acid  at  the  present  time 
is  in  the  treatment  of  acute  rheumatic  fever,  in  which  it  seems  to  have 
a  specific  action  only  excelled  by  that  of  quinine  in  malaria.  Other 
members  of  the  aromatic  series  have  some  effect  in  this  condition,  but 
none  of  them  equal  the  salicylic  preparations  in  efficacy.  Under  this 
treatment  the  pain  and  swelling  in  the  joints  rapidly  lessen,  the  tem- 
perature often  falls,  and  the  course  of  the  disease  is  shortened.  It  is 
still  debated  whether  the  salicylic  treatment  reduces  the  liability  to 
endocarditis  and  pericarditis,  which  are  common  complications  of  acute 
rheumatic  fever ;  some  clinicians  even  state  that  it  increases  the  risk 
of  these  complications,  while  others  advise  the  discontinuance  of  the 
treatment  when  any  symptoms  arise  from  the  heart.  The  view  more 
generally  entertained,  however,  is  that  the  cardiac  affections  are  less 
often  met  with  and  are  less  severe  under  salicylic  treatment,  and  very 
often  it  is  continued  in  small  quantities  even  after  the  heart  is  undoubt- 
edly involved  in  the  disease.  The  remedy  sometimes  fails  in  rheuma- 
tism, as  quinine  does  in  malaria,  and  it  sometimes  acts  more  satisfac- 
torily in  one  joint  than  in  another.  Large  doses  (1-2  G.  or  15-30 
grs.)  repeated  every  2-3  hours  are  necessary  in  some  cases  at  first,  the 
quantity  being  reduced  as  the  symptoms  abate.  Salicylic  acid  is  less 
frequently  used  than  the  salicylate  of  soda  or  salol,  but  some  clinicians 

'Salicylic  acid  has  been  used  very  largely  as  a  preservative  in  wine  and  beer.  No 
evil  effects  have  been  definitely  shown  to  follow  the  prolonged  use  of  liquors  thus 
treated,  but  it  is  not  impossible  that  they  may  be  injurious,  and  several  governments 
have  found  it  advisable  to  prohibit  its  use  for  this  purpose. 


ANTISEPTICS   OF  THE  AROMATIC  SERIES.  415 

hold  that  the  acid  is  the  most  efficient  of  the  three.  Oil  of  winter- 
green  may  also  be  used  here,  but,  like  salicylic  acid,  is  more  liable  to 
cause  gastric  irritation.  When  high  fever  is  present  the  antipyretic 
combinations  of  salicylic  acid,  such  as  malakine,  may  be  used  with 
advantage.  Salicin  is  less  disturbing  to  the  stomach  than  the  other 
preparations,  but  is  less  certain  in  its  effects  and  has  to  be  given  in 
larger  quantities. 

Salicylic  acid  has  also  been  used  in  the  various  forms  of  disease 
which  are  roughly  classified  as  rheumatic  —  chronic  rheumatism,  arth- 
ritis, neuralgia,  myalgia  —  but  the  effects  are  less  satisfactory  than  in 
acute  rheumatism.  The  lithium  salt  is  contained  in  the  U.  S.  P. 
because  lithium  is  erroneously  credited  with  a  special  solvent  action  on 
the  uric  acid  in  these  diseases. 

In  other  acute  constitutional  diseases  accompanied  by  fever,  salicylic 
acid  is  of  less  value  than  in  acute  rheumatism  so  that  it  would  appear 
that  it  has  a  specific  action  on  the  unknown  cause  of  this  malady. 

Salicylic  acid  in  some  cases  promotes  the  absorption  of  effusions  into 
the  serous  membranes,  such  as  the  pleura,  and  also  subretinal  effusion. 
It  is  unknown  how  this  is  effected,  but  it  scarcely  seems  probable  that 
the  slight  diuretic  action  of  the  drug  is  sufficient  to  account  for  it. 

The  cholagogue  action  of  the  salicylates  is  quite  inconsiderable  in 
comparison  with  that  of  the  bile  itself,  and  in  any  case  in  which  an 
increase  of  the  bile  secretion  is  desirable,  recourse  should  be  had  rather 
to  the  latter.  It  has  recently  been  suggested  by  Kuhn  that  the  salic- 
ylic salts  excreted  in  the  bile  may  retard  the  growth  of  microbes  and 
thus  prove  of  value  in  the  treatment  of  liver  and  gall-bladder  infections. 

The  solubility  of  the  salicylates  and  their  rapid  absorption  precludes 
their  use  as  intestinal  antiseptics,  but  salol  has  been  used  to  lessen 
putrefaction  in  the  bowel,  and  even  to  act  upon  the  bacilli  of  typhoid 
fever  and  of  tubercle  infecting  the  intestinal  wall.  Kumagawa,  how- 
ever, states  that  the  putrefaction  in  the  bowel  as  measured  by  the  in- 
dican  in  the  urine  is  unchanged  by  its  administration,  and  he  found 
enormous  numbers  of  bacteria  in  the  fa3ces  afterwards.  It  certainly 
seems  of  little  value  in  typhoid  fever  or  in  tuberculosis  of  the  intes- 
tine. Intestinal  calculi  have  been  formed  in  a  few  instances  from 
prolonged  treatment  with  salol,  which  failed  to  be  decomposed  in  the 
intestine  and  formed  masses  of  considerable  size. 

Salol  was  at  one  time  supposed  to  be  absorbed  only  after  its  de- 
composition in  the  intestine  by  the  pancreatic  juice,  and  Ewald  there- 
fore suggested  its  use  as  a  means  of  diagnosing  stenosis  of  the  pylorus. 
He  supposed  that  in  cases  in  which  the  food  was  delayed  or  prevented 
from  passing  into  the  intestine,  the  reaction  of  salicylic  acid  in  the 
urine  would  appear  correspondingly  late  or  be  entirely  absent.  But 
some  salol  seems  to  be  absorbed  from  the  stomach,  and,  on  the  other 
hand,  the  interval  between  its  administration  and  the  appearance  of  the 
salicylic  reaction  in  the  urine  is  so  variable  in  normal  individuals 
that  the  test  is  of  little  value.  Salol  has  been  used  to  coat  pills  and 
prevent  their  solution  in  the  stomach. 


presums 

Methyl  salicylate,  or  oil  of  wintergreen,  is 
muscular   and   articular   rheumatism,   it   beiil 
quantities  thus  reach  the  focus  of  disease  thai 
by  the  mouth.     Absorption  certainly  occurs| 
proved  by  the  appearance  of  salicyluric  acid 
tion  of  the  skin  is  liable  to  be  excited,  and 
is  doubtful  in  these  diseases.1 

BIBLIOGRAPHY. 

Kolbe.     Journ.  f.  pract.  Chemie,  x.,  p.  89  ;  xi.,  p.  9 ; 
Quincke.     Berl.  klin.  Woch.,  1882,  p.  709. 
Charted  and  McLennan.     Brit.  Med.  Journ.,  1889,  ii. 
Bauer  u.  Kiinstle.     Deutsch.  Arch.  f.  klin.  Med.,  xxr 
Sassetzky.     Virchow's  Arch.,  xciv.,  p.  485. 
Huber.     Deutsch.  Arch.  f.  klin.  Med.,  xli.,  p.  129. 
Maragliano.     Zts.  f.  klin.  Med.,  xvii.,  p.  291,  and  xiv. 
Gottlieb.    Arch.  f.  exp.  Path.,  xxvi.,  p.  436. 
Baumann.     Zts.  f.  phys.  Chem.,  i.,  p.  253. 
Binz.    Arch.  f.  exp.  Path.  u.  Pharm.,  vii.,  p.  280, 
Luthje.     Deutsch.  Arch.  f.  klin.  Med.,  Ixxiv.,  p.  163. 
Kleineberger  and  Oxenius.     Ibid.,  Ixxx.,  p.  225. 
Kuhn.     Mtinchener  Med.  Woch.,  1904,  p.  1457. 
Nencki.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvi.,  p.  40] 
Bochefontaine.     Comptes  rendus  d.  1.  Soc.  de  Biol., 
de  1' Academic,  Ixxxv.,  p.  574;  Ixxxvii.,  p.  657. 

Mosso.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvi.,  p.  267. 

C.  Virchow.     Zts.  f.  physiol.  Chem.,  vi.,  p.  78. 

Buss.     Deutsch.  Arch.  f.  klin.  Med.,  xv.,  p.  457. 

Baelz.     Arch.  d.  Heilkunde,  xviii.,  p.  60. 

Pfaff.     Jour,  of  Exp.  Med.,  ii.,  p.  49. 

Gaglio.     Arch.  Ital.  de  Biol.,  xxxi.,  p.  304. 

Schreiber  u.  Zandy.     Deutsch.  Arch.  f.  klin.  Med.,  Ixii.,  p.  242. 

Goodbody.     Journ.  of  Physiol.,  xxv.,  p.  399. 

Ulrici.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi.,  p.  321. 

Salol. 

Nencki.     Arch.  f.  exp.  Path.  u.  Pharm.,  xx.,  p.  367. 
Lesnik.     Ibid.,  xxiv.,  p.  167. 

1Mesotan,  or  methoxymethylsalicylate,  has  been  introduced  as  a  substitute  for  oil  of 
wintergreen  in  external  treatment,  but  has  no  advantages  of  any  consequence  over  the 
older  drug. 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  417 

Hesselbach.     Practitioner,  xlv.,  p.  12. 
Sahli.     Therap.  Monats.,  1887,  p.  333. 
EwaJd  u.  Sievers.     Ibid.,  p.  289. 
Marshall     Brit.  Med.  Journ.,  1897,  ii.,  p.  78. 

Salicin. 

Marme.     Gottingen.  Nachricht.,  1878,  p.  229. 
Maclagan.     Lancet,  1876,  i.,  p.  342. 
Senator.     Berl.  klin.  Woch.,  1877,  p.  181. 

Aspirin. 

Dreser.  Pfliiger's  Archiv,  Ixxvi.,  p.  306. 

Singer..  Ibid.,  Ixxxiv.,  p.  527. 

Gazert.  Deutsch.  Arch.  f.  klin.  Med.,  Ixviii.,  p.  142. 

Other  Aromatic  Oxy- acids. 

The  two  isomers  of  salicylic  acid,  meta-  and  para-oxybenzoic  acid,  are  said  to 
be  almost  devoid  of  antiseptic  properties,  and,  although  some  doubt  may  be 
entertained  as  to  the  correctness  of  this  statement,  they  have  never  been  used 
in  medicine  except  experimentally. 

The  cresotinic  acids  resemble  salicylic  acid  in  their  effects,  and  the  para- 
cresotinate  of  soda  has  been  used  occasionally  as  an  antipyretic  and  substi- 
tute for  salicylic  acid.  The  metacresotinate  is  very  much  less  active,  while 
the  orthocresotinate  possesses  a  dangerous  action  on  the  heart.  The  para- 
cresotinate  is  somewhat  less  poisonous  than  salicylic  acid.  The  cresotonic 
acids  are  found  as  impurities  in  some  commercial  specimens  of  salicylic  acid, 
but  these  ought  not  to  be  used  for  internal  administration,  as  the  presence  of 
the  orthocresotonic  acid  may  affect  the  heart. 

The  alpha-  and  beta-oxynaphtoic  acids  are  possessed  of  antiseptic  proper- 
ties, which  are  said  to  be  somewhat  greater  than  those  of  carbolic  and  sali- 
cylic acids,  but  they  are  less  soluble  in  water,  while  the  sodium  salt  is  less 
antiseptic.  The  acids  are  irritant  and  produce  diarrhoea  and  symptoms 
similar  to  those  of  salicylic  acid.  They  seem  to  be  at  least  as  poisonous  as 
carbolic  acid,  and  have  been  used  as  external  antiseptics  only  to  a  very 
limited  extent. 

BIBLIOGRAPHY. 

Suss.     Berl.  klin.  Woch.,  1876,  p.  445. 

Demme.     Therap.  Monats.,  1890,  p.  191. 

ffenne.     Inaug.  Diss.,  Bern,  1890. 

Charteris.     Brit.  Med.  Journ.,  1891,  i.,  p.  695. 

Ellenberger  u.  Hofmeister.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiv.,  p.  261. 

Wittenz.     Therap.  Monatsheft,  1888,  p.  20. 

Sulphocarbolates. 

The  sulphon  group  lessens  the  toxicity  in  the  same  way  as  carboxyl,  and 
the  sulphocarbolates  or  para-phenol-sulphonates  are  therefore  less  poisonous 
than  carbolic  acid.  The  sulphocarbolates  of  sodium  and  zinc  have  been  used 
as  external  antiseptics,  and  the  sulphocarbolate  of  sodium  has  been  adminis- 
tered to  arrest  fermentation  in  the  stomach.  The  zinc  salt  possesses  some 
astringent  action  and  has  been  used  with  good  results  as  an  injection  in  gon- 
orrhoea. The  sodium  salt  is  probably  excreted  in  the  urine  unchanged. 
Aseptol  or  sozolic  acid  is  a  33  per  cent,  solution  of  orthophenol-sulphonic 
acid  in  water  but  very  often  contains  some  of  the  para-acid. 

Sodii  Sulphocarbolas  (B.  P.),  Sodii  Phenolsulphonas  (U.  S.  P.),  or  sodium  para- 
phenol-sulphonate  (C6H4OHSO2ONa,2H2O),  forms  colorless,  transparent  prisms, 
without  odor,  and  with  a  saline  taste.  Soluble  in  5  parts  of  water.  0. 3-1  G. 
(5-15  grs.). 

Zinci   Sulphocarbolas  (B.  P.)   (Zn(OHC6H4SO3)2H2O)  forms   colorless,  trans- 
parent,  efflorescent  crystals,  which   are  very  soluble   in  water  and  in  alcohol 
27 


418  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION, 

BIBLIOGRAPHY. 

Serrant.     Comptes  rendus  de  PAcadem.,  c..  pp.  1465  and  1544. 
Hueppe.     Berl.  klin.  Woch.,  1886,  p.  609. 
Samter.     Inaug.  Diss.,  Berlin,  1887. 

Benzole  Acid. 

Benzoic  acid  possesses  almost  the  same  action  as  salicylic  acid  in 
the  body,  and  like  it,  is  poisonous  only  in  comparatively  large  quanti- 
ties. It  seems  to  be  equally,  or  according  to  some  observers,  more 
strongly  antiseptic,  and  like  salicylic  acid  irritates  the  mucous  mem- 
branes, while  its  salts  are  practically  devoid  of  this  last  property. 
Benzoic  acid  is,  however,  apparently  less  stimulant  to  the  central 
nervous  system,  and  the  characteristic  affections  of  the  hearing  and 
sight  have  not  been  observed  under  it. 

In  man,  very  large  quantities  of  benzoic  acid  and  also  of  the  ben- 
zoate  of  soda  sometimes  produce  nausea  and  vomiting,  the  vomited 
matter  rarely  being  tinged  with  blood.  A  certain  sedative  action  on 
the  central  nervous  system  is  also  said  to  be  observed,  and  an  increased 
expectoration  of  mucus  is  produced  in  cases  of  bronchial  irritation. 
The  pulse  is  somewhat  accelerated. 

In  the  dog,  tremors  and  convulsions  have  been  observed,  but  are 
generally  less  marked  than  under  carbolic  acid.  Ataxia,  paresis,  and 
eventually  complete  paralysis  of  the  fore  limbs,  and  later  of  the  hind 
limbs  and  trunk  follow,  the  temperature  falls,  and  death  occurs  from 
asphyxia.  The  heart  and  respiration  are  first  accelerated  and  then 
slowed,  from  a  direct  action  on  the  heart  and  on  the  respiratory  centre. 
Vomiting  occurs  when  the  acid  or  the  salts  are  given  by  the  mouth. 
Post-mortem  the  gastric  mucous  membrane  has  been  found  to  be 
eroded  and  ecchymosed,  even  when  the  salts  or  acid  have  been  injected 
subcutaneously  or  intravenously,  so  that  the  benzoates  and  benzoic 
acid  would  seem  to  have  a  specific  action  on  the  gastric  mucous  mem- 
brane quite  apart  from  their  irritant  effects  when  applied  locally. 

In  frogs,  fibrillary  contractions  and  convulsions  are  observed,  followed 
by  weakness  and  paralysis  of  the  spinal  cord.  Hemorrhages  have 
also  been  found  in  the  stomach  when  the  drug  was  injected  into  a 
lymph-sac. 

Benzoic  acid  (C6H5COOH)  combines  with  glycocoll  in  the  body  to 
form  hippuric  acid  (C6H5CO  —  NHCH2COOH),  which  is  excreted  in 
the  urine.  Some  of  the  benzoic  acid  escapes  in  the  urine  unchanged, 
however,  the  proportion  of  hippuric  acid  formed  apparently  varying 
with  the  general  health  and  the  condition  of  the  kidneys,  and  also  with 
the  dose  administered.  After  large  doses  a  reducing  body  has  been 
observed  in  the  urine,  presumably  glycuronic  acid.  Traces  of  benzoic 
acid  are  found  in  the  saliva  of  the  dog  after  its  administration,  but  it 
does  not  seem  to  be  excreted  here  in  man.  In  birds,  benzoic  acid  is 
excreted  by  the  kidneys  as  ornithuric  acid  (C19H20N2O4),  from  which 
benzoic  acid  can  be  split  off,  leaving  ornithin.  Benzoic  acid  often  in- 
creases the  nitrogen  eliminated  in  the  urine,  so  that  in  these  cases  it 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  419 

augments  the  decomposition  of  the  proteids  like  salicylic  acid ;  in 
other  investigations  no  material  change  has  been  observed,  probably 
because  the  benzoic  acid  was  changed  too  rapidly  to  hippuric  acid  to 
admit  of  its  action  on  the  metabolism  being  developed.  It  differs  from 
salicylic  acid  in  reducing  the  uric  acid  excretion.  Some  diuresis  occurs 
after  benzoic  acid. 

Some  diminution  in  the  double  sulphates  and  the  indican  of  the 
urine  have  been  observed  after  the  administration  of  benzoic  acid  by 
the  mouth,  so  that  it  apparently  lessens  the  putrefaction  in  the  in- 
testine. 

Cinnamic  acid  (C6H5-CH=CH-COOH)  seems  to  resemble  ben- 
zoic acid  in  its  pharmacological  characters,  but  has  not  been  so  care- 
fully examined.  It  increases  the  leucocytes  of  the  blood  and  the  uric 
acid  of  the  urine  to  a  marked  degree. 

PREPARATIONS. 

ACTDUM  BENZOICUM  (U.  S.  P.,  B.  P.)  (C6H5COOH),  benzoic  acid  or  flowers 
of  benzoin,  is  prepared  from  benzoin  by  sublimation,  or  from  toluol,  and 
consists  of  white,  feathery  crystals,  almost  odorless,  with  a  warm  acid 
taste,  very  insoluble  in  water,  soluble  in  alcohol,  ether,  fixed  and  volatile 
oils  and  in  alkaline  solutions.  0.3-1  G.  (5-15  grs.),  in  powder  or  pill. 

Trochiscus  Acidi  Benzolci  (B.  P.),  each  contains  \  gr. 

Sodii  Senzoas  (U.  S.  P.,  B.  P.),  easily  soluble  in  water.  0.3-2  G.  (5-30 
grs.),  in  solution. 

Lithii  Benzoas  (U.  S.  P.),  0.3-2  G.  (5-30  grs.). 

Ammonii  Benzoas  (U.  S.  P.,  B.  P.),  0.3-2  G.  (5-30  grs.). 

Benzoic  acid  is  also  contained  in  paregoric. 

The  Balsams  are  mixtures  of  resin,  volatile  oils,  benzoic  and  cinnamic 
acids  and  their  esters  and  small  quantities  of  other  aromatic  bodies. 

Benzoinum  (U.  S.  P.,  B.  P.),  benzoin,  a  balsam  obtained  from  Styrax  Ben- 
zoin and  probably  from  other  species,  varies  in  its  composition  with  its  place 
of  origin,  but  contains  much  less  cinnamic  acid  than  the  other  balsams. 

Styrax  (U.  S.  P.),  Styrax  Pr&paratus  (B.  P.),  or  storax,  a  balsam  prepared 
from  the  inner  bark  of  Liquidambar  orientalis,  contains  resins,  cinnamic 
acid  and  its  esters. 

Tinctura  Benzoini  (U.  S.  P.),  2-4  c.c.  (30-60  mins.). 

TINCTURA  BENZOINI  COMPOSITA  (U.  S.  P.,  B.  P.)  contains,  in  addition  to 
benzoin,  storax,  aloes  and  balsam  of  Tolu,  and  was  formerly  known  as  Bal- 
samum  Traumaticum.  A  number  of  old  remedies  resembled  it  in  composi- 
tion, such  as  Friar's  balsam,  Turlington's  balsam,  Jesuits'  drops,  etc.  2-8 
c.c.  (30  mins. -2  fl.  drs.). 

BALSAMUM  PERUVIANUM  (U.  S.  P.,  B.  P.),  Balsam  of  Peru,  a  balsam  ob- 
tained from  Toluifera  Pereirse  (U.  S.  P.),  or  Myroxylon  Pereirse  (B.  P.),  con- 
tains cinnamic  and  benzoic  acids  (traces)  and  their  esters,  and  resins.  Ap- 
plied externally,  either  alone  or  in  alcoholic  solution.  0.3-1  c.c.  (5—15 
mins.). 

Balsamum  Tolutanum  (U.  S.  P.,  B.  P.),  Balsam  of  Tolu,  a  balsam  obtained 
from  Toluifera  Balsamum  or  Myroxylon  Toluifera,  resembles  balsam  of  Peru 
in  composition,  but  contains  more  benzoic  acid.  0.3-1  G.  (5-15  grs.). 

SYRTJPUS  TOLUTANUS  (U.  S.  P.,  B.  P.),  2-4  c.c.  ($-1  fl.  dr.). 

Tinctura  Tolutana  (U.  S.  P.,  B.  P.),  1-4  c.c.  (15-60  mins.). 

Therapeutic  Uses.  —  Benzoic  acid  and  its  sodium  salt  have  been  sug- 
gested as  antiseptics  and  seem  to  be  quite  as  satisfactory  as  salicylic 


420  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

acid,  but  have  never  been  widely  employed.  Benzoin  and  the  balsam 
of  Peru  are  used  extensively  in  parasitic  skin  diseases,  especially  in 
scabies.  Internally  the  benzoates  have  been  employed  as  substitutes 
for  salicylic  acid  in  acute  rheumatism,  but  have  not  proved  so  efficient 
in  general.  The  lessened  putrefaction  in  the  bowel  after  benzoic  acid 
suggests  its  use  as  an  intestinal  disinfectant,  and  it  has  been  adminis- 
tered as  an  antiseptic  and  slight  irritant  in  diseases  of  the  genito-uri- 
nary  tract,  such  as  cystitis  and  gonorrhea.  It  was  formerly  supposed 
that  benzoic  acid  lessened  the  uric  acid  excretion  and  dissolved  the  uric 
acid  deposits  in  the  bladder  and  tissues  by  forming  hippuric  acid,  but 
this  is  now  recognized  to  be  erroneous,  and  the  treatment  of  gout  and 
other  diseases  based  on  this  theory  may  be  considered  obsolete.  The 
lithium  benzoate  of  the  U.  S.  P.  is  a  survival  of  this  treatment,  lithium 
being  credited  with  special  solvent  properties. 

Benzoic  acid  is  still  used  as  an  ingredient  in  expectorant  mixtures, 
in  which  however  it  is  generally  prescribed  as  the  simple  or  com- 
pound tincture  of  benzoin,  or  as  one  of  the  Tolu  preparations.  It  is 
said  to  be  beneficial  in  cases  in  which  the  mucus  is  tenacious  and  is 
coughed  up  with  difficulty.  The  syrup  of  Tolu  may  be  regarded 
simply  as  a  flavoring  ingredient,  for  it  contains  too  little  of  the  balsam 
to  have  any  other  effect. 

Balsam  of  Peru  and  pure  cinnamic  acid  have  been  administered  by  hypo- 
dermic and  intravenous  injection  and  by  the  mouth  in  pulmonary  tubercu- 
losis, in  the  belief  that  they  would  induce  irritation,  inflammation  and 
subsequent  cicatrization  of  the  tubercular  nodules,  but  there  is  no  reason  to 
suppose  that  they  have  any  such  effect,  and  the  treatment  has  never  ad- 
vanced beyond  the  experimental  stage. 

When  the  balsams  are  administered  in  large  quantities,  the  addition  of  an 
acid  to  the  urine  is  followed  by  the  formation  of  an  abundant  precipitate  in 
some  cases,  and  this  has  given  rise  to  the  belief  that  they  tend  to  irritate  the 
kidneys.  The  precipitate  appears  to  be  not  albumin  but  the  resin  in  most 
cases,  however,  for  it  is  dissolved  by  the  addition  of  alcohol. 

BIBLIOGRAPHY. 

Robert  u.  Schulte.     Schmidt's  Jahrb.,  clxxxv.,  p.  12. 

Salkowski.     Festschr.  f.  Leyden,  ii.,  p.  25. 

C.  Virchow.     Ztschr.  f.  phys.  Chem.,  vi.,  p.  78. 

Stockman.     Brit.  Med.  Journ.,  1890,  i.,  p.  1365. 

Kumagawa.     Virchow's  Arch.,  cxiiL,  p.  134. 

Brdutigam  u.  Nowack.     Centralbl.  f.  klin.  Med.,  1889,  p.  409. 

Richter  u.  Spiro.     Arch.  f.  exp.  Path.  u.  Pharm.,xxxiv.,  p.  289. 

Wiener.     Ibid.,  xl.,  p.  313. 

Pribram.     Ibid.,  1L,  p.  372. 

Lewandowsky.     Ztschr.  f.  klin.  Med.,  xl.,  p.  202. 

Ulrici.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi.,  p.  321. 

Nitrobenzol  Compounds. 

The  nitrobenzol  bodies  are  chiefly  of  interest  because  they  have  often  given 
rise  to  poisoning  of  late  years  from  their  extensive  use  in  chemical  manufactures 
and  to  flavor  alcoholic  liquors.  They  are  readily  absorbed  from  the  skin  and  seri- 
ous symptoms  have  followed  the  wearing  of  clothing  dyed  with  them.  In  man 
nitrobenzol  causes  a  grayish-blue,  cyanotic  color  of  the  skin  and  visible  mucous 
membranes,  often  with  nausea,  vomiting,  great  muscular  weakness,  marked 


ANTISEPTICS  OF  THE  AROMATIC  SERIES.  421 

dyspnoea,  delirium,  and  some  convulsive  movements  of  the  face  and  jaws, 
less  frequently  of  the  whole  body.  Total  unconsciousness  and  coma  are 
followed  by  arrest  of  the  respiration. 

These  effects  are  due  in  part  to  changes  in  the  blood,  in  part  to  central 
nervous  action,  in  which  stimulation  and  paralysis  seem  to  follow  one  another. 
The  blood  is  found  of  a  chocolate-brown  color,  and  some  of  the  red  cells  are 
either  deformed  or  entirely  destroyed.  Examined  with  the  spectroscope, 
methaBmoglobin  is  very  often  found  in  it,  while  in  other  cases  an  absorption 
line  is  observed  between  the  yellow  and  the  red,  which  does  not  seem  to  corre- 
spond to  that  of  any  of  the  ordinary  hemoglobin  products,  and  has  there- 
fore been  called  the  nitrobenzol-ha3moglobin  line.  The  blood  contains 
a  much  smaller  amount  of  oxygen  than  normally,  in  some  cases  only 
one  per  cent,  instead  of  seventeen,  and  artificial  respiration  or  even  shaking 
the  blood  in  air  fails  to  oxidize  it  further,  as  the  combination  of  nitrobenzol 
and  haemoglobin  seems  to  be  incapable  of  absorbing  oxygen.  Similar  changes 
may  be  produced  in  venous  blood  outside  the  body  by  shaking  it  with  nitro- 
benzol. These  changes  in  the  blood  are  the  cause  of  the  cyanosis,  and  the 
imperfect  oxidation  of  the  tissues  leads  to  the  appearance  of  a  number  of 
abnormal  products  in  the  urine,  such  as  haematoporphyrin.  In  animals  a  gastro- 
intestinal catarrh  is  almost  constantly  produced  unless  the  intoxication  is  very 
acute,  and  this  occurs  even  when  the  poison  is  inhaled  or  injected  subcutaneously. 

Metadinitrobenzol  (C6H4(NO2)2)  has  repeatedly  given  rise  to  poisoning  in 
the  manufacture  of  the  modern  explosives,  such  as  roburite  and  securite.  In 
action  it  resembles  nitrobenzol,  but  is  more  poisonous,  and  the  gastric  symp- 
toms are  more  marked.  Amblyopia  and  a  jaundice  like  coloration  of  the 
skin  often  occur  from  prolonged  exposure  to  this  poison. 

Picric  Acid  (C6H2OH(NO2)3)  is  an  irritant  to  the  skin  and  mucous  mem- 
branes, and  in  large  doses  causes  vomiting  and  often  anuria  and  strangury. 
A  characteristic  symptom  is  the  yellow,  icteric  color  of  the  skin  and  mucous 
membranes,  which  is  due  not  to  true  jaundice,  but  to  the  staining  of  the 
epithelium  by  the  acid.  It  produces  this  coloration  when  taken  internally, 
and  itching  is  often  complained  of,  and  some  eczema  or  erythema  has  been 
observed.  Violent  convulsions  occur  sometimes,  in  other  cases  collapse. 
The  urine  is  yellow  or  red,  and  contains  some  casts  but  little  or  no  albumin, 
and  no  bile,  the  absence  of  the  last  serving  to  diagnose  the  intoxication 
from  jaundice.  Picric  acid  tends  to  destroy  the  red  cells  of  the  blood  in 
animals,  but  no  marked  diminution  of  these  has  been  observed  in  man.  It 
is  excreted  as  picric  and  picramic  acid  (C6H2OH.NH2(NO2)2)  in  the  urine. 

Picric  acid  has  been  used  as  a  substitute  for  quinine  in  malaria,  and  as  an 
antipyretic.  An  ointment  containing  it  has  been  applied  in  some  forms  of 
eczema,  but  it  gave  rise  to  poisoning  in  one  of  the  few  cases  in  which  it  was 
thus  employed. 

BIBLIOGRAPHY  OF  THE  AROMATIC  NITRO-BODIES. 

Starkow.     Virchow's  Arch.,  lii.,  p.  464. 

Hay.     Practitioner,  xxx.,  p.  326. 

Filehne.     Arch.  f.  exp.  Path.  u.  Pharm.,  ix.,  p.  329. 

Lewin.     Virchow's  Arch.,  Ixxvi. ,  p.  443. 

Stone.     Jour.  Amer.  Med.  Ass.,  Oct.  1, 1904. 

Schroederu.  Strassman.     Viertlj.  f.  ger.  Med.,  1891,  i.,  Suppl.,  p.  138. 

Seek.     Charite  Annalen,  xvii.,  p.  867. 

Munzeru.  Palma.     Zts.  f.  Heilk.,  xv.,  p.  185. 

Huber.     Virchow's  Arch.,  cxxvi.,  p.  240. 

Naphthylamine. 

Stern  has  observed  a  curious  and  almost  unique  series  of  symptoms  after 
fae  administration  of  several  hydrated  derivatives  of  /3-naphthylamine  to 
mammals.  The  most  interesting  of  these  were  dilation  of  the  pupil  and 


422  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

protrusion  of  the  eyeball,  and  a  very  marked  rise  in  the  temperature, 
amounting  in  some  cases  to  4£°  C.  The  dilation  of  the  pupil,  which  was 
not  observed  in  the  later  experiments  of  Fawcett  and  White,  is  ascribed  by 
Stern  partly  to  local  action  on  the  dilator  fibres  or  the  terminations  of  the 
sympathetic  nerves  in  the  iris,  but  mainly  to  some  central  stimulation.  The 
rise  of  temperature  is  produced  in  part  by  the  output  of  heat  being  lessened 
through  contraction  of  the  cutaneous  vessels,  in  part  by  increased  oxidation 
in  the  tissues  and  augmented  heat  production.  The  contraction  of  the  vessels 
is  to  be  attributed  chiefly  to  stimulation  of  the  vaso-motor  centres,  although 
the  drug  seems  to  have  some  direct  effect  on  the  muscular  walls  of  the  vessels 
also.  Cocaine  has  a  somewhat  similar  but  weaker  action,  but  the  naphthyl- 
amine  compounds  do  not  produce  local  anesthesia. 

BIBLIOGRAPHY. 

Stern.     Virchow's  Arch.,  cxv.,  p.  34,  and  cxxi.,  p.  376. 
Fawcett  and  White.     Journ.  of  Physiol.,  xxi.,  p.  435. 

Toluylendiamine. 

Toluylendiamine  (C6H3CH3(NH2)2)  has  never  been  used  in  therapeutics, 
but  it  is  of  importance  from  the  light  which  it  has  thrown  on  some  forms  of 
jaundice.  Stadelmann  found  that  its  administration  in  dogs  produced  the 
typical  symptoms  of  icterus,  while  in  cats  the  icterus  was  less  marked,  but 
very  large  quantities  of  haemoglobin  were  excreted  in  the  urine.  The  expla- 
nation of  this  action  is  the  destruction  of  the  red  cells  in  the  blood,  which 
leads  in  the  dog  to  the  formation  of  large  amounts  of  bile  pigments  in  the 
liver.  Some  of  this  pigment  is  reabsorbed  from  the  bile  vessels  and  leads  to 
typical  jaundice.  The  absorption  is  promoted  by  a  curious  increase  in  the 
mucus  secretion  of  the  bile  ducts,  which  renders  the  bile  more  viscous,  and 
by  thus  delaying  its  evacuation  into  the  intestine  favors  its  absorption  into 
the  blood.  This  increased  mucus  formation  is  believed  to  be  due  to  the 
action  of  the  poison  on  the  secretory  cells  of  the  larger  bile  ducts.  The 
formation  of  bile  pigment  from  haemoglobin  liberates  large  quantities  of  iron, 
which  seems  to  be  stored  in  the  liver,  spleen  and  bone  marrow.  In  the  cat 
the  haemoglobin  is  not  so  largely  formed  into  bile  pigment,  but  escapes  in 
the  urine.  In  both  animals  some  methaemoglobin  is  probably  formed.1 

BIBLIOGRAPHY. 

Stadelmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiv.,  pp.  231  and  422;  xxiii.,  p.  427. 
Engel  u.  Kiener.     Comptes  rend,  de  1'Acad.,  cv.,  p.  465. 
Mohrberg.     Arb.  a.  d.  pharm.  Inst.  zu  Dorpat,  viii.,  p.  20. 

Benzol. 

Benzol,  or  benzene,  is  much  less  poisonous  than  its  hydroxyl  com- 
pounds, but  may  give  rise  to  symptoms  resembling  those  of  phenol  when  it 
is  inhaled  in  large  quantities.  It  was  at  one  time  suggested  as  a  general  an- 
aesthetic, but  the  preliminary  excitement  is  very  much  greater  than  that  seen 
in  the  use  of  chloroform  or  ether,  and  partakes  much  more  of  a  convulsive 
character.  Even  after  unconsciousness  and  anaesthesia  is  attained,  the  char- 
acteristic muscular  tremor  of  the  aromatic  compounds  continues.  In  some 
animals  it  produces  violent  and  prolonged  convulsions,  with  only  partial  loss 
of  sensation,  and  even  large  quantities  do  not  cause  the  complete  relaxation 
of  the  muscles  requisite  for  surgical  operation.  It  seems  to  have  little  or  no 
irritant  action  on  the  alimentary  canal  or  kidneys  in  animals,  and  is  excreted 

1 A  somewhat  similar  action  follows  the  administration  of  Cephalanthin,  the  active 
principle  of  Cephalanthus  occidentalis,  Button-bush  or  Swamp  dogwood  (Mohrberg). 


FORMALDEHYDE.  423 

in  part  by  the  kidneys  as  phenol  double  sulphate,  in  part  unchanged  by  the 
lungs. 

Santesson  states  that  haemorrhages  occur  very  frequently  in  fatal  poison- 
ing in  man,  and  found  the  same  result  in  experiments  on  rabbits  ;  he  ascribes 
it  to  fatty  degeneration  of  the  arterial  walls,  which  was  well-marked  in  most 
of  his  experiments.  A  number  of  cases  of  fatal  intoxication  are  on  record, 
some  of  them  arising  from  the  drug  being  swallowed  by  suicides,  but  most  of 
them  from  the  accidental  inhalatipn  of  large  quantities  in  india-rubber  fac- 
tories. Animals  exposed  to  benzol  vapor  do  not  seem  to  absorb  enough  to  be 
seriously  poisoned,  but  when  it  is  injected  subcutaneously  or  applied  over  a 
large  skin  area,  it  proves  fatal  to  them.  The  benzol  of  the  B.  P.  contains 
toluene  and  is  used  only  for  pharmaceutical  purposes. 

BIBLIOGRAPHY. 

Santesson.     Arch.  f.  Hygiene,  xxxi.,  p.  336.     Skand.  Arch.  f.  Physiol.,  x.,  p.  1. 
Chassevant.     Arch,  de  Pharmacody  nam. ,  ii.,  p.  235. 

Pyoctanine. 

Several  of  the  dyes  derived  from  aniline  are  used  to  stain  pathogenic  germs 
and  to  differentiate  them  from  each  other.  This  suggested  to  Penzoldt  the 
idea  that  these  bodies,  having  a  distinctly  greater  affinity  for  the  microorgan- 
isms than  for  the  tissues  surrounding  them,  might  be  used  as  antiseptics  or 
disinfectants,  and  Stilling  introduced  several  of  them  into  therapeutic  use 
under  the  name  of  pyoctanines.  Some  of  these  dyes  have  been  found  to 
have  a  certain  antiseptic  action ,  but  the  hopes  that  were  formerly  entertained 
as  to  their  specific  action  have  proved  delusive,  and  their  use  in  medicine 
(chromotherapeutics)  is  now  very  limited,  and  promises  to  fall  into  oblivion. 

MethylthionincB  Hydrochloridum  (U.  S.  P.),  methylene  blue,  a  dark  green  pow- 
der, readily  soluble  in  water  and  alcohol,  forming  a  deep  blue  solution.  Dose, 
0.25G.  (4grs.). 

XXV.     FORMALDEHYDE. 

It  has  recently  been  shown  by  numerous  investigators  that  formal- 
dehyde (HCOH),  the  aldehyde  derived  from  the  oxidation  of  methyl 
alcohol,  is  a  very  powerful  germicide,  while  it  is  only  slightly  poison- 
ous to  the  higher  animals.  The  aldehyde  is  a  colorless  gas  and  has 
been  used  either  in  solution  in  water  (formaline)  or  as  a  vapor.  As  a 
germicide  it  is  estimated  to  be  equally  efficient  with  corrosive  subli- 
mate, and  its  volatility  enables  it  to  penetrate  much  more  rapidly,  so 
that  it  may  be  used  for  purposes  for  which  the  latter  is  unsuitable.  On 
the  other  hand,  its  volatility  and  irritant  action  preclude  its  use  as  an 
antiseptic  to  prevent  the  growth  of  microbes  in  wounds. 

Action.  —  The  vapor  is  very  irritant  when  inhaled,  causing  stinging 
and  prickling  in  the  nose  and  throat,  salivation  and  tears,  and  bronchial 
irritation  and  catarrh.  In  the  few  cases  of  poisoning  in  man  recorded, 
the  symptoms  were  those  of  gastric  irritation  and  consequent  collapse. 
When  swallowed  by  animals  the  watery  solution  produces  nausea  and 
vomiting,  which  are  followed  by  narcosis,  coma,  and  in  the  rabbit  by 
convulsions  and  opisthotonos.  The  respiration  in  the  dog  is  very 
greatly  accelerated  some  time  before  death,  while  in  the  rabbit  this  is 
not  so  marked  or  is  entirely  absent.  The  blood-pressure  is  increased 
at  first  and  the  heart  is  slow,  presumably  from  direct  or  indirect  stimu- 
lation of  the  medullary  centres.  Part  of  the  formaldehyde  absorbed 


424  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

has  been  shown  to  pass  through  the  tissues  unchanged  and  to  be 
excreted  in  the  urine,  and  it  is  possible  that  the  whole  of  it  escapes  in 
this  way.  The  symptoms  induced  in  animals  by  formaldehyde  are  for 
the  most  part  due  to  the  intense  local  irritation  and  inflammation,  but 
in  addition  a  specific  destructive  effect  has  been  observed  in  the  liver 
and  kidney  (Fischer). 

The  powerful  action  of  formaldehyde  on  microbes  and  on  mucous 
membranes  is  believed  by  Loew  to  be  due  to  its  combining  with  some 
amide  group  in  the  proteids,  and  as  a  matter  of  fact,  a  number  of 
changes  have  been  described  in  the  reaction  of  proteids  exposed  to 
formaline.  For  example,  egg  albumin  and  serum  to  which  formal- 
dehyde solution  has  been  added  are  not  precipitated  by  heat  and  are 
less  easily  digested  by  ferments,  while  casein  is  not  coagulated  by  the 
rennet  ferment.  Some  of  the  ferments  (pepsin  and  diastase)  are  not 
affected  by  the  presence  of  formaldehyde,  while  trypsin  and  papain 
lose  their  activity  wholly  or  in  part. 

Benedicenti  states  that  formaldehyde  is  a  blood  poison,  causing  alter- 
ation in  the  form  of  the  cells  and  leading  to  the  formation  of  haematin. 
He  is  disposed  to  look  upon  this  effect  as  the  chief  factor  in  the  in- 
toxication. 

PKEPARATIONS. 

Formalin,  LIQUOR  FORMALDEHYDI  (U.  S.  P.),  a  solution  of  formaldehyde  in 
water  containing  not  less  than  37  per  cent,  of  the  gas,  which  may  be  obtained 
from  it  by  distillation. 

Paraform,  a  solid  polymer  of  formaldehyde,  which  is  decomposed  by  heat 
and  liberates  the  formaldehyde  in  gaseous  form. 

Some  formaldehyde  may  be  formed  by  the  incomplete  combustion  of  methyl 
alcohol,  and  several  lamps  have  been  devised  with  this  object  in  view,  but  have 
not  proved  entirely  satisfactory. 

Uses.  —  Formaldehyde  is  too  irritant  to  admit  of  its  use  as  an  anti- 
septic in  medicine  and  surgery,  but  it  has  been  largely  employed  to 
disinfect  instruments,  furniture,  clothes  and  rooms,  which  cannot  be 
sterilized  by  heat.  Diluted  formaline  (4  per  cent.)  may  be  used  for 
some  of  these  purposes,  or  the  vapor  may  be  disengaged  by  distillation 
from  formaline,  by  heating  paraform,  or  less  efficiently  by  the  partial 
combustion  of  methyl  alcohol.  Large  rooms  filled  with  formaline 
vapor  and  left  for  some  hours  are  found  to  be  almost  completely  steril- 
ized, so  that  cultures  of  the  pathogenic  microbes  exposed  in  them  cease 
to  grow  even  when  removed  from  the  atmosphere.  The  higher  animals 
are  much  less  affected.  Novy  recommends  that  the  room  to  be  disin- 
fected be  made  as  nearly  air-tight  as  possible,  and  the  formaldehyde  be 
distilled  into  it  through  the  key-hole  of  the  door.  He  states  that  the 
gas  disengaged  from  150  c.c.  (5  oz.)  of  40  per  cent,  formaline  is  suffi- 
cient for  each  1000  cubic  feet  of  space,  if  the  room  be  closed  for  10 
hours.  The  odor  of  formaline  may  then  be  removed  by  sprinkling 
ammonia  solution  with  which  it  forms  a  solid  combination. 

Formaldehyde  has  frequently  been  added  to  food,  especially  to  milk, 
as  a  preservative.  Tunnicliffe  and  Rosenheim  found  that  added  to  milk 
in  the  proportion  of  one  to  five  thousand,  formaldehyde  did  not  seem 


FORMALDEHYDE.  425 

to  be  deleterious  to  healthy  children,  but  in  the  case  of  a  weakly  child 
the  proteid  waste  was  increased,  and  it  is  certainly  not  to  be  regarded 
as  a  harmless  method  of  preserving  food. 

Formaldehyde  is  not  alone  in  its  germicidal  action,  although  it  is  much 
more  powerful  than  the  other  less  volatile  and  less  active  aldehydes,  such  as 
acetaldehyde. 

Urotropine. 

Urotropine,  or  hexamethylenamine  ((CH2)6N4),  has  no  important 
action  itself,  but  is  of  interest  from  its  liberating  formaldehyde  in  the 
course  of  its  excretion  by  the  kidney.  The  formaldehyde  escapes  in 
the  urine  along  with  some  unaltered  urotropine,  and  acts  as  a  disin- 
fectant or  antiseptic  in  the  urinary  passages ;  it  seems  superior  to  any 
other  urinary  antiseptic,  microbes  in  the  urine  decreasing  in  number  or 
sometimes  disappearing  altogether  within  a  few  hours  of  its  adminis- 
tration. No  symptoms  arise  from  ordinary  doses  of  urotropine,  but 
large  quantities  have  occasionally  given  rise  to  pain  and  discomfort  in  the 
bladder,  and  more  rarely  to  haematuria.  Formaldehyde  forms  some  sol- 
uble combinations  with  uric  acid,  and  this  suggested  the  use  of  urotro- 
pine in  gravel,  calculus,  gout,  and  similar  conditions,  but  the  results 
have  been  disappointing. 

HEXAMETHYLENAMINA  (U.  S.  P.),  UROTROPINE  ((CH2)6N4),  is  a 
white  crystalline  powder,  very  soluble  in  water.  Dose,  0.2—0.6  G. 
(3-10  grs),  to  be  taken  in  a  glass  of  water. 

Urotropine  is  used  in  cystitis  and  urethritis  and  to  destroy  typhoid 
bacilli  in  cases  in  which  they  are  eliminated  by  the  kidney.  It  may 
also  be  given  as  a  prophylactic  before  a  catheter  is  passed. 

Numerous  compounds  of  urotropine  have  been  introduced  of  late  years  by  rival 
manufacturers,  but  none  of  these  has  proved  equal  to  the  original  drug. 

BIBLIOGRAPHY. 

Loew.     Ein  natiirliches  System  der  Giftwirkungen,  Miinchen,  1893,  p.  58. 

Koch.     Amer.  Journ.  of  Phystol.,  vi.,  p.  327. 

Fischer.     Journ.  of  Exp.  Med.,  vi.,  p.  487. 

Dieudonne.     Arbeit,  a.  d.  Gesundlieitsamt.,  xi.,  p.  534. 

Mosso  et  Paoletti.     Arch.  Ital.  de  Biol.,  xxiv.,  p.  321. 

Tollens.     Bericht.  der  Deuts.  Chem.  Gesellsch.,  1895,  p.  261. 

Pohl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi.,  p.  295. 

Ermengem  et  Sugg.     Arch,  de  Pharmacodynam.,  i.,  p.  141. 

Armison.     Zts.  f.  Hygiene,  xxv.,  p.  168,  1897. 

Strilver.     Ibid.,  p.  357. 

Benedicenti.     Arch.  f.  [Anat.  u.]  Phys.,  1897,  pp.  210  and  219. 

Novy  and  Waite.     Medical  News,  Ixxii.,  p.  641  (1898). 

.Bliss  and  Novy.     Journ.  of  Exp.  Med.,  iv.,  p.  47. 

Tunnicli/e  and  Rosenheim.     Journ.  of  Hygiene,  i.,  p.  321. 

Urotropine. 

Nicolaier.  Zts.  f.  klin.  Med.,  xxxviii.,  p.  350 ;  Deutsch.  Arch.  f.  klin.  Med.,  Ixxxi., 
p.  181. 

Stern.     Leyden's  Festschrift,  1902,  i.,  p.  583. 
Richardson.     Journ.  of  Exp.  Med.,  iv.,  p.  19. 
Sachs.     Wien.  klin.  Woch.,  1902,  p.  442. 
Fuchs.    Ibid.,  1903,  p.  170. 


426  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

XXVI.  CAMPHOR. 

Some  of  the  volatile  oils  deposit  crystalline  substances  or  stearop- 
tenes  after  standing  for  some  time,  especially  when  they  are  exposed 
to  cold.  As  a  general  rule  these  bodies  are  present  in  only  small 
amount,  and  have  not  been  investigated  apart  from  the  volatile  oils, 
of  which  they  form  constituents  ;  but  a  few  of  them  have  attracted  at- 
tention in  therapeutics,  not  only  on  account  of  their  local  effects,  which 
have  been  described  under  the  volatile  oil  group  (see  page  61),  but 
also  because  of  their  action  in  the  tissues  after  absorption.  The  chief 
of  these  is  Camphor,  which  has  been  used  in  Chinese  medicine  for 
many  centuries,  and  which  has  also  played  a  considerable  role  in 
Western  therapeutics.  It  is  derived  from  the  Cinnamomum  camphora 
of  China  and  Japan,  and  possesses  the  formula  C10H1GO ;  it  is  a  benzol 
derivative  containing  methyl  and  propyl,  in  so  far  resembling  the 
terpenes,  from  which,  however,  it  differs  in  the  presence  of  a  ketone 
(=  CO)  link. 

Another  body  closely  resembling  ordinary  camphor  is  Borneol  or  Borneo- 
camphor  (C10H1KO),  which  is  derived  from  the  Dryobalanops  aromatica,  and 
which  apparently  differs  from  ordinary  camphor  in  containing  the  group 
(=  CHOH)  instead  of  (=  CO).  Ngai- camphor,  which  is  obtained  from  Blumea 
balsamifera,  is  very  closely  related  to  borneol.  Another  stearoptene  which 
has  been  used  in  medicine  apart  from  the  volatile  oils,  is  Menthol  (C10H20O), 
which  is  obtained  from  the  oil  of  peppermint,  and  apparently  contains  a 
CHOH  group  like  borneol,  but  is  more  completely  hydrated.  Borneol  has 
been  prepared  synthetically  from  camphor,  and  menthol  from  menthane, 
which  occurs  in  oil  of  peppermint.  Thujon,  an  isomer  of  camphor,  occurring 
in  the  oil  of  wormwood  or  absinth  and  in  many  other  plants,  has  not  been  used 
in  medicine,  but  is  of  great  importance  as  the  cause  of  epilepsy  in  chronic  absinth 
drinkers. 

Several  derivatives  of  camphor  which  have  been  examined,  resemble  it 
closely  in  pharmacological  action.  Monobromated  Camphor  (C10H15BrO)  has 
been  used  in  therapeutics,  while  Camphorol  (C10H16O2),  Camphoric  Acid 
(CSHU(COOH)2),  Amidocamphor  (C10H15NH2O),  Sorm/lamine  (C8HU(CH2)- 
(CHNH2))  and  some  other  derivatives  have  been  the  subjects  of  experi- 
mental investigation. 

All  of  these  resemble  each  other  very  closely  in  the  effects  which 
they  produce  in  the  organism,  although  they  vary  in  toxicity  to  some 
extent.  Many  of  the  volatile  oils  induce  the  same  symptoms,  but  as 
these  are  used  almost  exclusively  for  their  local  action,  it  has  been 
found  advisable  to  treat  them  separately.  The  camphor  group  pre- 
sents analogies  to  the  simpler  bodies  of  the  aromatic  series,  to  which  it 
is  so  nearly  related  chemically,  and  also  to  picro toxin. 

Symptoms.  —  Camphor  acts  as  an  irritant  to  the  skin  and  mucous 
membranes  like  the  volatile  oils,  and  has  a  hot,  bitter  taste,  and  induces 
in  small  quantities  a  feeling  of  warmth  and  comfort  in  the  stomach, 
while  after  large  doses  nausea  and  vomiting  may  be  caused  by  gastric 
irritation.  It  is  rapidly  absorbed  and  in  large  doses  induces  headache, 
a  feeling  of  warmth,  confusion,  and  excitement  in  man,  with  slowing  of 
the  pulse  and  flushing  of  the  skin.  This  excitement  may  be  shown  in 


CAMPHOR.  427 

hilarity  and  delirium  with  hallucinations,  in  restlessness,  or  in  sudden 
violent  movements,  which  pass  into  epileptiform  convulsions.  These 
alternate  with  pauses  of  quiet  and^mconsciousness,  which  become  longer 
until  the  patient  sinks  into  complete  stupor.  In  some  cases  of 
poisoning  no  excitement  is  observed,  the  patient  falling  into  a  condi- 
tion of  drowsiness,  unconsciousness  and  stupor  immediately.  In  the 
lower  mammals,  camphor  induces  very  similar  symptoms,  wild  excite- 
ment and  epileptiform  convulsions,  followed  by  depression,  stupor, 
collapse,  and  death  from  failure  of  the  respiration.  Not  infrequently 
however,  the  respiration  ceases  during  a  convulsion  and  fails  to  return 
when  it  passes  off. 

In  the  frog  no  excitement  is  observed  except  from  the  local  irri- 
tation ;  the  animal  falls  into  a  condition  of  depression,  in  which  no 
spontaneous  movements  are  made,  although  the  reflexes  seem  to  be 
little  affected  at  first.  Later,  the  reflexes  disappear  and  the  animal 
lies  completely  paralyzed. 

Action  :  Central  Nervous  System. — Camphor  first  depresses  the  brain 
in  the  frog,  later  the  spinal  cord,  and  last  of  all  the  terminations  of  the 
motor  nerves,  and  the  spontaneous  movements  cease  first,  therefore, 
then  the  reflexes  disappear,  and  finally  the  muscles  fail  to  contract  when 
the  peripheral  nerves  are  stimulated.  The  cord  is  capable  of  conduct- 
ing impulses  from  the  brain  after  the  reflexes  are  paralyzed,  so  that 
camphor  would  seem  to  interrupt  the  connection  between  the  sensory 
and  the  motor  cells  earlier  than  that  between  the  motor  columns  and 
the  cells  of  the  anterior  horn  (contrast  strychnine).  Although  camphor 
fails  to  elicit  convulsions  in  the  frog,  thujon  often  induces  violent 
spasms,  which  appear  to  arise  from  stimulation  of  the  spinal  cord  and 
medulla  oblongata.  The  exact  action  of  camphor  on  the  spinal 
cord  in  mammals  is  not  finally  determined,  for  Stockman  found 
that  the  reflexes  were  not  increased  in  mammals  by  camphor,  and 
he  holds  that  the  spinal  cord  is  not  primarily  stimulated  by  ordinary 
camphor,  and  is  in  fact  depressed  by  borneol.  On  the  other  hand, 
Gottlieb  and  Lapin  assert  that  the  reflexes  are  increased  by  camphor 
in  mammals  in  which  the  medulla  oblongata  has  been  divided,  and 
that  in  the  bird  this  increased  irritability  may  even  give  rise  to  con- 
vulsions. According  to  them,  the  spinal  cord  is  finally  depressed  in 
mammals  by  very  large  doses  of  camphor,  but  only  after  stupor  and 
coma  indicate  commencing  paralysis  of  the  cerebrum. 

The  convulsions  in  mammals  are  certainly  not  due  to  any  action  on 
the  spinal  cord,  but  to  stimulation  of  the  higher  areas  of  the  nervous 
axis.  The  cerebral  cortex  is  involved  in  the  action,  for  the  convulsions 
are  less  marked  on  its  removal ;  but  in  the  lower  mammals  the  chief 
action  seems  to  be  exerted  on  the  nervous  centres  situated  between  the 
cerebral  peduncles  and  the  medulla  oblongata.  It  is  not  improbable 
that  in  man  the  cerebral  action  may  be  more  marked  than  that  on  the 
lower  areas,  for  on  descending  lower  in  the  scale  it  is  found  that  the  cere- 
bral action  becomes  less  evident ;  thus  in  birds  the  removal  of  the  cere- 
brum seems  to  have  no  effect  on  the  convulsions.  The  loss  of  con- 


428  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

sciousness  and  the  stupor  observed  in  man  and  the  higher  animals 
point  to  a  final  paralysis  of  the  cerebral  cortex. 

The  Terminations  of  the  Motor  Nerves  are  paralyzed  in  the  frog  by 
large  doses  of  camphor,  but  not  in  mammals.  The  Muscles  them- 
selves are  weakened  and  paralyzed  when  they  are  directly  exposed  to 
its  solutions  or  vapor. 

The  Heart  is  sometimes  slowed  by  camphor  and  its  allies  in  man  and 
animals,  but  is  generally  little  affected  in  either  strength  or  rate.  The 
frog's  heart  also  beats  more  slowly,  but  the  contractions  are  stronger 
and  fuller  according  to  most  observers,  although  Lewin  found  both  its 
absolute  force  and  pulse  volume  lessened ;  these  changes  arise  from 
action  on  the  muscle  fibres,  which  are  rendered  more  irritable,  so  that 
muscarine  fails  to  arrest  the  frog's  heart  after  camphor  (compare 
physostigmine,  pp.  320,  324). 

In  some  mammals  the  Blood-pressure  is  slightly  increased  by  cam- 
phor, in  others  great  variations  occur,  a  very  marked  rise  being  observed 
during  the  convulsive  attacks,  while  in  the  interval  it  falls  to  below  the 
normal  height ;  these  variations  indicate  that  the  vaso-motor  centre  is 
involved  in  the  action  of  the  drug,  for  they  persist  when  the  muscular 
contractions  are  eliminated  by  the  injection  of  curara.  The  peripheral 
vessels  have  been  found  to  be  dilated  by  camphor  solutions  perfused 
through  them,  and  this  action  may  explain  the  slight  fall  in  pressure 
often  seen  after  absorption  of  the  drug. 

This  slight  dilatation  of  the  vessels  is  the  only  change  in  the  circu- 
lation observed  after  camphor,  unless  when  quantities  sufficient  to 
cause  convulsions  are  injected. 

The  Respiration  is  somewhat  slower  and  deeper  than  normal,  but  this 
alteration  is  generally  insignificant.  During  the  convulsions  it  is  ar- 
rested, and  in  the  intervals  may  be  accelerated  from  the  muscular  ex- 
ertion during  the  spasms. 

The  normal  Temperature  is  not  affected  by  camphor,  but  in  fever  it 
acts  as  an  antipyretic,  like  many  other  aromatic  bodies. 

Camphor  is  partially  oxidized  in  the  tissues,  forming  camphorol 
(C10H16O2),  this  change  perhaps  being  analogous  to  that  observed  in  the 
aromatic  hydrocarbons  and  phenols.  It  is  Excreted  in  the  urine1  in 
combination  with  glycuronic  acid,  as  a-  and  /9-camphoglycuronic  acid, 
and  also  in  part  in  combination  with  a  nitrogenous  body,  which  is  prob- 
ably uramidoglycuronic  acid.  Camphorol  acts  like  camphor,  but  its 
glycuronic  acid  combinations  are  inactive,  so  that  the  effects  of  cam- 
phor pass  off  quickly  in  such  animals  as  the  dog,  in  which  these  com- 
binations are  rapidly  formed. 

Camphor  is  possessed  of  some  antiseptic  action,  although  it  is  much 
weaker  than  some  of  the  bodies  of  the  carbolic  acid  group,  and  also 
than  many  of  the  volatile  oils.  Leucocytes  cease  their  movements  at 
once  when  exposed  to  camphor  solutions  or  vapor,  and  Darwin  found 
that  it  acts  as  a  stimulus  to  the  tentacles  of  Drosera,  an  insectivorous 

1  Menthol  is  said  to  be  excreted  in  small  quantities  in  the  bile. 


CAMPHOR.  429 

plant,  and  apparently  renders  them  more  sensitive  to  mechanical  irri- 
tation. 

Camphor  produces  redness  and  a  feeling  of  warmth  when  rubbed 
into  the  Skin.  Sometimes,  however,  a  distinct  sensation  of  cold  may 
be  experienced,  provided  the  rubbing  is  not  too  energetic.  Menthol 
generally  induces  this  feeling  of  cold,  accompanied  by  more  or  less 
prickling,  and  afterwards  by  heat  and  burning.  The  cold  is  not  due 
to  cooling  of  the  skin,  for  the  vessels  of  the  part  are  dilated,  and  the 
thermometer  indicates  a  higher  skin  temperature  there  than  in  other 
parts  of  the  body.  It  has  been  ascribed  to  menthol  being  more  irritant 
to  the  terminations  of  certain  nerves  which  convey  the  sensation  of 
cold  than  to  those  of  the  heat  nerves  and  pain  nerves,  but  this  is  denied 
by  Rollett  who  states  that  menthol  acts  only  on  the  terminations  of  the 
nerves  of  common  sensation  or  pain.  A  feeling  of  numbness  and  par- 
tial anesthesia  follows  its  application  after  some  time,  and  a  ten  per 
cent,  solution  has  been  found  to  produce  anaesthesia  of  the  cornea, 
which,  however,  is  preceded  by  pain  and  smarting. 

The  action  of  borneol,  menthol,  bromated  camphor,  camphorol  and  cam- 
phoric acid  is  almost  identical  with  that  of  camphor  itself.  Borneol  is  less 
irritant  locally,  and  the  convulsions  are  less  severe  than  after  camphor,  so 
that  animals  seldom  die  during  the  convulsive  stage,  and  may  remain  in  a 
state  of  stupor  and  collapse  for  one  or  two  days  before  the  respiration  finally 
ceases.  After  menthol,  the  convulsions  are  even  less  developed  than  after 
borneol.  Both  of  these  are  excreted  in  combination  with  glycuronic  acid. 
Bromated  camphor  seems  to  resemble  borneol  more  closely  than  camphor  or 
menthol,  while  camphoric  acid  and  amido-camphor  produce  symptoms  sim- 
ilar to  those  of  camphor,  but  are  much  less  powerful.  Camphoric  acid 
lessens  the  secretion  of  perspiration  by  paralyzing  the  terminations  of  the 
secretory  nerves  in  the  same  way  as  atropine  and  agaricin. 

PREPARATIONS. 

Camphora  (U.  S.  P.,  B.  P.)  (C10H160),  Laurel  camphor,  a  stearoptene  ob- 
tained from  Cinnamomum  Camphora,  forms  white  translucent,  crystalline 
masses,  which  are  almost  insoluble  in  water  but  dissolve  readily  in  alcohol, 
ether,  chloroform,  fixed  and  volatile  oils.  0.1-0.6  G.  (2-10  grs.),  in  emulsion 
or  pill. 

Aqua  Camphors  (U.  S.  P.,  B.  P.). 

SPIRITUS  CAMPHORS  (U.  S.  P.,  B.  P.),  0.3-2  c.c.  (5-30  mins.). 

LINIMENTUM  CAMPHORS,  camphorated  oil  (U.  S.  P.,  B.  P.). 

TINCTURA  CAMPHORS  COMPOSITA  (B.  P.),  paregoric,  contains  1  part  of 
morphine  in  2000,  i.  e.,  each  fluid  drachm  is  equivalent  to  J-  grain  of  opium. 
i-1  fl.  dr. 

lAnimentum  Camphor se  Ammoniatum  (B.  P.),  compound  camphor  liniment. 

Camphor  is  also  an  ingredient  in  the  camphorated  tincture  of  opium,  or 
paregoric  (U.  S.  P.)  and  in  soap  liniment  and  chloroform  liniment. 

Camphora  Monobromata  (U.  S.  P.),  monobromated  camphor  (C10H15BrO), 
consists  of  colorless  crystals  which  are  insoluble  in  water,  soluble  in  alcohol 
and  ether.  0.3-1  G.  (5-15  grs.),  in  emulsion  or  pills. 

Menthol  (U.  S.  P.,  B.  P.)  (C10H20O),  a  stearoptene  obtained  from  the 
official  oil  of  peppermint  or  from  Japanese  or  Chinese  oil  of  peppermint,  con- 
sists of  colorless  crystals  slightly  soluble  in  water,  freely  soluble  in  alcohol 
or  ether.  It  is  used  externally  in  alcoholic  solution  or  moulded  into  sticks 
and  pencils,  which  are  rubbed  on  the  affected  part. 


430  OROANTC  DRUGS  ACTING  AFTER  ABSORPTION. 

Emplastrum  Menthol  (B.  P.). 

ACIDUM  CAMPHORICTJM  (U.  S.  P.)  (H2C10H14O4),  an  acid  obtained  by  the 
oxidation  of  camphor  ;  forms  colorless  crystals  slightly  soluble  in  water.  Dose, 
1-2  G.  ( 15-30  grs.). 

Borneol  or  Borneo  camphor  (C10H18O),  a  stearoptene  obtained  from  Dryo- 
balanops  Camphora,  resembles  camphor  in  appearance  and  solubility,  but 
has  not  been  used  in  therapeutics  and  is  not  official. 

Therapeutic  Uses.  —  Camphor  is  used  externally  in  the  form  of  the 
liniment  or  spirit  as  a  mild  rubefacient  in  bruises  and  sprains,  and 
also  to  destroy  parasites.  Internally  the  spirit  is  prescribed  as  a 
carminative  and  as  an  intestinal  disinfectant.  Its  administration  for 
the  latter  purpose  has  been  shown  to  be  followed  by  a  diminution  of 
the  double  sulphates  of  the  urine,  so  that  it  seems  to  retard  the  putre- 
faction in  the  bowel  to  some  extent.  The  spirit  is  frequently  given  to 
prevent  "  chill,"  and  may  relieve  the  congestion  of  internal  organs 
through  dilating  the  skin  vessels. 

It  was  formerly  administered  in  cases  of  abnormal  irritability  of 
the  central  nervous  system,  such  as  epilepsy  and  various  other  forms 
of  convulsions,  including  those  produced  by  strychnine,  but  its  action 
would  seem  to  contraindicate  its  use  here  and  camphor  is  scarcely 
prescribed  in  these  cases  now. 

It  has  been  used,  apparently  with  success,  as  a  stimulant  to  the  cen- 
tral nervous  system  in  unconsciousness  and  collapse  arising  from  dif- 
ferent causes,  and  in  the  depression  and  weakness  of  acute  fevers.  In 
many  of  these  cases,  a  marked  improvement  in  the  pulse  has  been  ob- 
served after  camphor ;  this,  like  the  similar  improvement  seen  after 
alcohol,  may  perhaps  be  explained  by  its  action  as  a  local  stomachic 
irritant  producing  changes  in  the  circulation  reflexly.  Solutions  of 
camphor  have  been  injected  subcutaneously  in  these  cases,  but  they 
cause  pain  and  swelling  at  the  point  of  injection.  Camphor  is  almost 
entirely  insoluble  in  watery  fluids  and  is  apparently  absorbed  slowly 
and  with  difficulty  in  some  conditions,  and  this  may  explain  the 
absence  of  effect  in  many  cases  of  collapse  treated  with  it. 

Camphor  is  often  prescribed  in  expectorant  mixtures,  especially  in 
combination  with  opium,  as  in  paregoric. 

It  has  been  advised  in  hysteria,  and  both  as  an  aphrodisiac  and  as 
an  anaphrodisiac.  Any  effect  in  these  conditions  must  probably  be 
ascribed  rather  to  hypnotic  suggestion  than  to  the  real  action  of  the 
drug. 

Menthol  is  used  almost  exclusively  for  its  effects  on  the  sensory  nerve 
terminations,  and  is  applied  by  rubbing  the  crystals  or  sticks  on  the 
skin  in  cases  of  headache  and  neuralgia. 

Camphoric  acid  has  been  found  to  lessen  the  night  sweats  of  phthisis 
and  is  given  for  this  purpose  in  powder  in  doses  of  1-2  G.  It  pos- 
sesses the  advantage  over  atropine  of  acting  only  on  the  sweat  glands 
in  the  dose  given,  and  on  the  other  hand  has  no  such  action  on  the 
digestion  as  is  sometimes  complained  of  when  agaricin  has  been  pre- 
scribed. Camphoric  acid  is  slowly  absorbed  and  ought  to  be  given  an 


PICROTOXIN.  431 

hour  or  more  before  retiring.     It  has  also  been  used  as  an  antiseptic, 
but  is  very  much  less  efficient  than  salicylic  or  carbolic  acid. 

Borneol  and  monobromated  camphor  are  entirely  superfluous.  The  latter  was 
at  one  time  used  as  a  sedative  in  nervous  excitement,  but  does  not  seem  to  have 
been  at  all  beneficial  and  has  fallen  into  disuse. 

BIBLIOGRAPHY. 

Hoffmann.     Inaug.  Diss.,  Dorpat,  1866. 

Rovighi.     Zts.  f.  phys.  Chem ,  xvL,  p.  20. 

Schmiedeberg  u.  Meyer.     Ibid.,  iii.,  p.  422. 

Stockman.    Journ.  of  Physiol.,  ix.,  p.  65.    Edinburgh  Med.  Journ.,  1897,  i.,  p.  45. 

Lewin.    Arch.  f.  exp.  Path.  u.  Pharra.,  xxvii.,  p.  226. 

Gottlieb.     Ibid.,  xxx.,  p.  31. 

Meyer.     Ibid.,  xxix.,  p.  438. 

Wiedemann.     Ibid.,  vi.,  p.  216. 

Goldscheider.     Arch.  f.  Anat,  u.  Phys.,  1886,  p.  555. 

Rollett.     Pfliiger's  Arch.,  Ixxiv.,  p.  418. 

JBourneville.     Practitioner,  xiii.,  p.  112. 

Lawson.     Ibid.,  xiii.,  p.  324 ;  xiv.,  p.  262. 

Lapin.     Inaug.  Diss.,  Dorpat,  1893. 

Winterberg.     Pfliiger's  Arch.,  xciv..  p.  455. 

Boehrn.   Inaug.  Diss.,  Halle,  1879.     (Absinth.) 

Magnan.     Compt.  rend,  de  1'Acad.,  Ixviii.,  p.  825.     (Absinth.) 

Hildebrandt.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlviii.,  p.  451.     (Thujon.) 

Musk,  or  moschus,  is  the  dried  secretion  of  the  preputial  follicles  of  Moschus 
moschiferus,  the  musk  deer  of  Thibet.  It  forms  a  dark,  reddish-brown,  crum- 
bling mass,  with  a  very  strong  characteristic  odor.  About  10  per  cent,  is  sol- 
uble in  alcohol,  about  50  per  cent,  in  water. 

Musk  has  long  been  reputed  to  have  a  very  powerful  action  in  collapse, 
but  is  so  rarely  procurable  at  the  present  day,  except  in  a  very  much  adul- 
terated form,  that  it  is  comparatively  seldom  used.  Very  little  is  known 
with  certainty  as  to  its  composition,  and  the  odoriferous  matter,  which  is 
believed  to  be  the  active  principle,  has  scarcely  been  examined. 

In  some  early  investigations,  musk  was  found  to  cause  headache,  giddiness 
and  confusion,  with  a  feeling  of  weight  and  uneasiness  in  the  stomach  ;  later, 
depression  and  drowsiness,  and  eventually  sleep.  Tremors  and  even  con- 
vulsive movements  have  also  been  observed,  and  the  pulse  is  said  to  be  ac- 
celerated and  strengthened. 

Filehne  found  tremors  and  contractions  of  isolated  muscle  bundles  pro- 
duced in  the  frog  from  the  action  of  an  extract,  and  concluded  that  the 
motor  terminations  were  stimulated  by  it.  On  the  other  hand,  Hermans,1 
who  studied  the  subject  more  recently,  could  find  no  effects  from  the  admin- 
istration of  musk  to  men  or  animals. 

Moschus  (U.  S.  P.,  B.  P.)  has  been  recommended  in  hysteria  and  in  col- 
lapse, and  is  prescribed  either  as  a  powder,  in  doses  of  0.5-1  G. ,  which  may 
be  given  per  rectum  when  swallowing  is  impossible,  or  in  the  form  of  the 
tincture  of  the  U.  S.  P.,  in  doses  of  5  c.c.  It  is  rarely  used  at  the  present 
time,  and  may  be  considered  entirely  superfluous. 

XXVII.     PICROTOXIN. 

Picrotoxin  is  the  best  known  member  of  a  group  of  convulsive  poi- 
sons, which  resemble  each  other  very  closely  in  action,  but  of  whose 
chemistry  little  is  known  beyond  the  fact  that  they  are  devoid  of 
nitrogen.  It  is  obtained  from  the  Anamirta  paniculata  (Anamirta 
cocculus,  Menispermum  cocculus),  and  is  a  neutral  indifferent  body. 
Picrotoxin  (C30H.MO13)  may  be  broken  up  into  picrotoxinin  (C15H16O6), 
Inaugural  Dissertation,  Bonn,  1888. 


i 


432  ORGANIC  DRUGS  ACTING   AFTER  ABSORPTION. 

which  resembles  it  in  its  effects  on  animals,  and  picrotin  (C15H18O7), 
which  is  inactive. 

Other  poisons  resembling  picrotoxin  are  Cicutoxln,  derived  from  the 
Cicuta  virosa,  or  water  hemlock,  and  probably  from  other  species  of  Cicuta, 
(Enanthotoxin,  the  active  principle  of  (Enanthe  crocata,  water  dropwort,  or 
dead  tongue,  and  Coriamyrtin,  which  occurs  in  several  species  of  Coriaria, 
of  which  the  best  known  is  the  Coriaria  myrtifolia  or  currier's  sumach. 
Another  species  of  Coriaria  affords  the  toot  poison  of  New  Zealand.  Phyto- 
laccotoxin,  which  has  been  prepared  irom  a  Japanese  species  of  Phytolacca, 
resembles  picrotoxin  in  its  action  and  may  probably  be  contained  in  the 
official  (U.  S.  P.)  Phytolacca  decandra,  or  pokeberry.  Lastly,  a  number 
of  the  members  of  the  digitalis  series  may  be  decomposed  into  bodies  which, 
devoid  of  the  characteristic  cardiac  action  of  digitalis,  produce  the  same 
symptoms  as  picrotoxin.  Among  these  may  be  mentioned  Toxiresin,  ob- 
tained from  digitoxin,  Digitaliresin  from  digitalin,  and  Oleandresin  from 
oleandrin.  These  bodies  all  produce  powerful  stimulation  of  the  central 
nervous  system,  more  especially  of  the  areas  around  the  medulla  oblongata. 
The  chemical  connection  between  them  and  the  members  of  the  digitalis 
series  has  been  mentioned  already.  It  may  be  added  that  the  two  groups 
are  similar  in  action  in  some  respects,  for  although  picrotoxin  does  not  affect 
the  heart  and  vessels  in  the  same  way  as  digitalis,  the  latter  possesses  the 
characteristic  action  of  picrotoxin  on  the  medulla  oblongata,  although  in  a 
weaker  degree  ;  in  fact,  some  of  the  remedies  described  under  the  digitalis 
series  act  as  strongly  on  the  central  nervous  system  as  on  the  heart.  Picro- 
toxin resembles  camphor  also  in  its  effects.  Two  alkaloids,  Samandarine  and 
Samandaridine,  recently  isolated  by  Faust  from  the  skin  of  the  newt  ap- 
pear to  resemble  picrotoxin  in  their  effects  on  animals. 

Symptoms.  —  The  symptoms,  which  are  often  somewhat  late  in  ap- 
pearing, are  very  similar  in  all  classes  of  vertebrates.  In  man  vom- 
iting is  not  infrequently  observed  after  members  of  this  series,  or  the 
first  symptoms  may  be  salivation,  acceleration  of  the  respiration,  and 
some  slowness  of  the  pulse  and  palpitation  of  the  heart.  A  condition 
of  stupor  and  unconsciousness  follows  and  then  a  series  of  powerful 
convulsions,  which,  commencing  in  tonic  spasms,  soon  change  to 
clonic  movements  of  the  limbs  and  jaws.  The  respiration  is  inter- 
rupted during  these  spasms,  but  is  reinstated  during  the  intervals  of 
quiet  and  collapse  which  follow  them.  The  convulsions  return  after 
a  short  pause,  and  this  alteration  of  spasm  and  quiet  may  continue  for 
some  time,  although  the  respiration  often  fails  to  return  after  one  of 
the  spasms,  and  fatal  asphyxia  results. 

Similar  effects  are  observed  in  the  lower  mammals.  After  a  pre- 
liminary stage  in  which  twitching  of  the  muscles  and  vomiting  often 
occur,  and  in  which  the  respiration  is  accelerated,  while  the  pulse  is 
slow,  a  violent  emprosthotonic  convulsion  sets  in,  but  soon  changes 
to  clonic  movements ;  these  may  last  for  some  time,  but  eventually 
become  weaker  and  give  place  to  a  condition  of  quiet  and  depression. 
An  increase  in  the  reflex  excitability  is  noticeable  during  this  interval, 
the  animal  is  easily  startled  and  occasional  twitching  of  the  muscles 
may  be  observed.  Very  soon  a  second  convulsion  sets  in,  and  this 
may  be  fatal  from  asphyxia,  but  the  symptoms  often  continue  for  an 
hour  or  more,  violent  spasms  alternating  with  periods  of  depression 
and  collapse.  In  the  frog  clonic  convulsions  are  also  the  chief  feature 


PICROTOXIN.  433 

of  the  intoxication.  Very  often  the  animal  becomes  distended  with 
air  during  the  convulsions,  and  gives  a  curious  cry  in  releasing  it. 
The  heart  is  always  slowed  and  may  cease  to  beat  altogether  for 
a  time. 

Action.  —  The  clonic  convulsions  of  picrotoxin  poisoning  are  al- 
together different  from  those  of  strychnine  and  other  similar  bodies, 
which  induce  prolonged  tonic  convulsions,  and  it  was  early  surmised 
that  the  members  of  this  series  act  on  a  different  part  of  the  Central 
Nervous  System.  The  convulsions  are  found  to  persist  in  the  frog 
after  the  cerebrum  has  been  destroyed,  and  even  when  all  of  the  brain 
above  the  medulla  oblongata  has  been  removed,  although  they  are 
weakened  by  the  destruction  of  the  optic  lobes.  On  the  other  hand, 
they  disappear,  or  at  any  rate  lose  their  typical  character  when  the 
medulla  oblongata  is  removed,  so  that  it  would  seem  that  picrotoxin  and 
its  allies  act  chiefly  on  the  medulla  oblongata,  while  the  spinal  cord  and 
the  higher  parts  of  the  brain  are  comparatively  little  affected.  Strych- 
nine, on  the  other  hand,  exercises  its  chief  action  on  the  spinal  cord, 
while  the  other  parts  of  the  central  nervous  axis  are  less  affected.  It 
was  formerly  supposed  that  picrotoxin  stimulated  a  "  convulsion  centre  " 
in  the  medulla  oblongata,  but  there  is  no  reason  to  believe  that  any  such 
definite  area  exists,  and  it  would  rather  appear  that  intense  stimulation 
of  the  medulla  in  general  leads  to  clonic  contractions  of  the  muscles 
throughout  the  body.  The  effects  of  the  stimulation  of  the  individual 
centres  in  the  medulla  are  seen  in  the  acceleration  of  the  respiration,  in 
the  slow  pulse,  which  is  due  to  inhibitory  action,  in  a  very  marked  rise 
of  the  blood-pressure,  and  in  the  vomiting  and  salivation.  The  medulla 
cblongata  is  not,  however,  the  exclusive  seat  of  action,  for  in  many 
animals  the  reflexes  are  found  to  be  increased  when  the  medulla  is 
severed  from  the  cord,  and  this  indicates  that  the  spinal  cord  is  also 
more  excitable  than  normally.  This  action  on  the  spinal  cord  is  best 
seen  in  the  fish  and  reptile,  and  is  much  less  marked  in  the  frog  and 
mammals.  In  the  former,  picrotoxin  causes  convulsions  even  after  the 
medulla  oblongata  is  removed,  but  in  the  higher  animals,  in  which  the 
functions  are  more  differentiated,  it  merely  increases  the  reflexes  or 
causes  very  slight  convulsive  movements  ;  and  the  higher  the  position 
in  the  scale  of  the  organism,  the  more  closely  is  the  action  of  this 
series  confined  to  the  medulla  oblongata. 

It  may  be  questioned  whether  the  higher  divisions  of  the  nervous 
axis  are  concerned  in  the  picrotoxin  intoxication,  for  though  in  some 
animals  restlessness  and  increased  spontaneous  movements  are  seen, 
they  may  perhaps  be  the  indirect  results  of  the  alterations  in  the 
respiration  and  circulation. 

The  Heart  is  rendered  slow  by  picrotoxin,  and  in  the  frog  may  come 
to  a  standstill  during  the  convulsions.  This  is  due  principally  to  stimu- 
lation of  the  inhibitory  centre  in  the  medulla,  since  on  division  of  the 
vagi  the  heart  returns  to  almost  its  normal  rate.  Some  direct  depres- 
sion of  the  heart  is  observed  after  large  doses,  for  the  pulse  remains 
slowed  even  after  atropine  or  division  of  the  vagi.  This  action  on  the 
28 


434  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

heart  is  not  similar  to  that  characteristic  of  digitalis,  as  has  been  sup- 
posed, but  is  a  paralysis  such  as  is  observed  after  many  poisons 
(e.  g.j  chloral).  In  some  cases  acceleration  of  the  heart  is  seen  towards 
the  end  of  the  intoxication,  and  this  has  been  supposed  to  be  due  to 
stimulation  of  the  accelerating  centre.  Picrotoxin  causes  a  very  marked 
rise  in  the  arterial  tension  from  stimulation  of  the  vaso-constrictor  cen- 
tres in  the  medulla  and  upper  part  of  the  cord. 

The  Respiration  is  accelerated  before  any  convulsions  set  in,  and  in 
the  intervals  between  the  spasms  is  also  very  rapid,  owing  to  the  action 
on  the  centre.  Late  in  the  intoxication  the  breathing  may  become 
slow  and  labored,  probably  from  approaching  central  paralysis.  In 
the  frog,  spasm  of  the  laryngeal  muscles  prevents  the  escape  of  air 
from  the  lungs,  so  that  the  animal  becomes  enormously  inflated. 

The  Vomiting  often  observed  in  man  and  the  dog  under  picrotoxin 
is  probably  of  central  origin  and  not  due  to  gastric  irritation. 

The  peripheral  Nerves  and  Muscles  do  not  seem  to  be  affected  by 
these  poisons,  with  the  exceptions  of  toxiresin  and  digitaliresin,  which 
slightly  lessen  the  irritability  of  the  muscles. 

The  fate  of  picrotoxin  in  the  body  and  the  way  in  which  it  is  ex- 
creted are  unknown.  Like  other  convulsive  poisons,  it  tends  to  lower 
the  temperature  when  it  is  given  in  small  quantities  so  that  no  con- 
vulsions follow. 

The  convulsions  of  picrotoxin  and  its  allies  disappear  when  chloro- 
form or  chloral  is  administered.  On  the  other  hand,  the  respiration, 
weakened  by  narcotic  poisons  such  as  chloral,  is  accelerated  by  picro- 
toxin, the  blood-pressure  rises,  and  the  sleep  is  less  prolonged.  Ani- 
mals are  not  awakened  at  once  from  narcosis  by  picrotoxin,  but  coria- 
myrtin  has  this  effect. 

Picrotoxin  is  not  antidotal  in  morphine  poisoning  in  animals,  but 
may  possibly  be  so  in  man  (see  page  213). 

PREPARATIONS. 

Picrotoxinum  (B.  P.),  picrotoxin  (C,0H84O18),  a  neutral  principle  obtained 
from  Anamirta  paniculata,  slightly  soluble  in  water,  much  more  so  in  alcohol. 
0.001-0. 003  G.  (<fo-*Vgr.)- 

Phytolacca  (U.  S.  P.),  the  root  of  Phytolacca  decandra,  or  pokeroot. 

Fluidextractum  Phytolaccce  (U.  S.  P.),  0.3-2  G. 

Therapeutic  Uses.  —  Picrotoxin  has  been  used  as  an  ointment  to 
destroy  pediculi,  and  in  some  forms  of  skin  disease,  but  is  too  poison- 
ous to  be  recommended  for  this  purpose.  It  has  been  proposed  to 
give  it  by  subcutaneous  injection  in  cases  of  collapse  and  in  narcotic 
poisoning,  but  according  to  Koppen,  coriamyrtin  is  more  efficient  in 
animals.  It  has  not  been  employed  for  this  purpose  in  therapeutics  as 
yet.  It  has  some  reputation  in  the  profuse  night-sweats  of  phthisis, 
which  it  diminishes  in  a  certain  proportion  of  cases,  probably  by  in- 
creasing the  respiration  and  thus  preventing  the  stimulation  of  the 
nervous  mechanism  of  perspiration  through  the  partial  asphyxia. 
Phytolacca  has  been  advised  as  an  emetic,  but  is  slow  in  action  and 
dangerous.  It  is  seldom  prescribed,  and  appears  to  be  superfluous, 
at  any  rate  until  its  action  has  been  ascertained  with  more  certainty. 


THE  DIGITALIS  SERIES.  435 

BlBLIOGEAPHY. 

Luchsinger.     Pfliiger's  Arch.,  xvi.,  p.  530. 

Marshall.     Pharm.  Journal,  Aug.  16,  1902.     (Root  poison.) 

Browne.     Brit.  Med.  Journal,  1875,  i.,  p.  409. 

Koppen.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix.,  p.  327. 

Gottlieb.     Ibid.,  xxx.,  p.  21. 

Harnack.     Ztsch.  f.  klin.  Med.,  xxv.,  p.  16. 

Boehm.     Arch.  f.  exp.  Path.  u.  Pharm.,  iii.,  p.  224;  v.,  p.  279.     (Cicutoxin.) 

PohL     Ibid.,  xxxiv.,  p.  259.     (Cicutoxin  and  GEnanthotoxin. ) 

Perrier.     Ibid.,  iv.,  p.  191.     (Toxiresin,  Digitaliresin,  etc.) 

Faust.     Ibid.,  xli.,  p.  229;  xliii.,  p.  84.     (Samandarin.) 

XXVIII.     THE  DIGITALIS  SERIES. 

The  digitalis  series  embraces  a  considerable  number  of  substances 
which  are  characterized  by  their  action  on  the  heart.  They  are  widely 
distributed  in  the  vegetable  kingdom  in  very  different  botanical  fam- 
ilies, and  have  long  been  in  use  for  various  purposes  in  civilized  and 
uncivilized  countries.  Some  of  them  were  employed  as  remedies  by 
the  laity  long  before  their  virtues  were  recognized  by  the  medical  pro- 
fession, while  others  have  been  used  as  arrow  poisons  by  the  natives  of 
different  parts  of  Africa  and  of  the  Eastern  Archipelago. 

The  most  important  plants  which  contain  bodies  belonging  to  this 
group  are  Digitalis  purpurea  (purple  foxglove),  Strophanthus  hispidus, 
or  Kombe,  and  Scilla  maritima  (squills).  Others  wrhich  are  less  fre- 
quently used  are  Helleborus  niger l  (Christmas  rose),  Convallaria  ma- 
jalis  (lily  of  the  valley),  Apocynum  cannabinum  (Canadian  hemp),  and 
Adonis  vernalis  (pheasant's  eye).  Similar  effects  are  obtained  from 
bodies  contained  in  other  species  of  these  genera  and  in  a  large  and 
ever-growing  list  of  other  plants,  such  as  Antiaris  (Upas  tree),  Nerium 
(oleander),  Acocanthera  (ouabaio),  Erythrophloeum  (sassy  bark  or  Casca 
bark),  Thevetia,  Urechites  and  Coronilla.2  Numbers  of  other  plants 
are  said  to  resemble  digitalis  in  their  effects,  but  until  this  has  been 
shown  by  more  careful  investigation,  it  is  undesirable  to  add  them  to 
the  above  list,  which  is  already  extensive  enough.  Many  of  the  arrow 
poisons  certainly  contain  digitalin  bodies,  but  even  their  botanical 
origin  is  unknown  in  many  instances.  These  bodies  are  not,  however, 
confined  to  the  vegetable  kingdom,  for  Faust  has  recently  isolated  two 
substances  3  from  the  skin  of  the  toad,  which  induce  the  same  changes 
in  the  heart,  and  the  Epinephrine  of  the  suprarenal  capsule  (see  supra- 
renal gland)  has  been  recently  shown  to  have  very  similar  effects. 
Salts  of  barium  also  induce  many  of  the  changes  characteristic  of  this 
series. 

The  active  principles  of  the  plants  of  this  group  present  many  points 
of  resemblance,  and  some  of  them  which  are  now  believed  to  be  distinct 
may  prove  to  be  identical.  Their  isolation  is  attended  with  consider- 
able difficulty,  as  many  are  amorphous,  and  but  few  of  them  form 

1  This  must  not  be  confused  with  green  and  white  hellebore  (see  page  338). 

2  Cactus  grandiflorus  (Cereus),  which  has  been  recommended  as  a  substitute  for  digi- 
talis, has  no  similar  action  and  does  not  belong  to  this  series. 

3  These  are  named  Bufonin  and  Bufotalin  and  appear  to  be  nearly  related  to  choles- 
terin. 


436  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

combinations  with  the  ordinary  chemical  reagents.  Most  of  them  are 
glucosides,  others  are  indifferent  bodies,  and  one  or  two  are  alkaloids. 
There  are  often  found  in  a  plant  several  distinct  bodies  belonging  to 
this  series,  and  these  may  again  be  accompanied  by  others  which  in- 
duce the  same  symptoms  as  picrotoxin  or  saponin. 

Digitalis  has  been  more  carefully  examined  from  the  chemical  point 
of  view  than  the  other  plants,  but  even  its  active  principles  are  still 
only  partially  known,  and  the  subject  is  yet  in  an  unsatisfactory  state ; 
for  the  amount  and  character  of  the  active  constituents  seem  to  vary 
not  only  in  different  seasons  and  in  plants  grown  in  different  soils,  but 
also  in  different  parts  of  the  same  plant.  The  chief  active  principles 
were  isolated  by  Schmiedeberg  in  1874  and  his  statements  have  more 
recently  been  confirmed  and  extended  by  Kiliani.  There  appear  to 
be  at  least  four  glucosides  in  digitalis  which  possess  the  characteristic 
cardiac  action  —  Digitoxin,  Digitophyllin,  Digitalin  and  Digitalein — 
and  these  are  accompanied  by  one  or  more  glucosides  (Digitonin)  which 
have  the  irritant  action  of  saponin  and  like  it  suspend  insoluble  bodies 
in  water.  The  pharmacopoeial  preparations  are  made  from  the  leaves, 
in  which  digitoxin  and  digitophyllin  are  the  most  important  constitu- 
ents, though  a  small  quantity  of  another  glucoside  resembling  digitalin 
is  also  present.  These  glucosides  are  practically  insoluble  in  water 
when  pure,  but  are  taken  up  from  the  leaves  by  water  owing  to  the 
presence  of  the  digitonins,  so  that  the  infusion  of  digitalis  leaves  is  a 
very  powerful  preparation.  The  active  glucosides  are  more  soluble  in 
alcohol,  while  digitonin  is  insoluble,  so  that  the  tincture  contains  prac- 
tically the  same  constituents  as  the  infusion  except  digitonin. 

The  seeds  of  digitalis  are  not  pharmacopoeial,  but  are  extensively 
used  for  the  preparation  of  the  so-called  digitalines  of  commerce.  They 
contain  digitalin  and  digitalein  in  large  amounts  with  a  small  percen- 
tage of  digitoxin  and  a  larger  proportion  of  digitonins  than  the  leaves. 
Digitalin  is  less  insoluble  in  water  than  digitoxin  and  digitalein  is 
freely  soluble.  The  preparations  from  the  seeds  thus  differ  entirely 
from  the  Galenical  preparations  which  are  formed  exclusively  from  the 
leaves,  and  most  clinicians  find  them  less  satisfactory  in  practice. 
Digitoxin  is  much  the  most  powerful  constituent,  and  the  small  amount 
in  which  it  is  present  in  the  digitalines  prepared  from  the  seeds  prob- 
ably accounts  for  their  unsatisfactory  effects  in  therapeutics. 

Strophanthus  Kombe  contains  a  crystalline  glucoside,  strophanthin, 
while  other  varieties  of  strophanthus,  such  as  S.  hispidus,  contain 
another  glucoside,  pseudo-strophanthin,  which  is  probably  nearly  related 
to  strophanthin  but  is  about  twice  as  poisonous.  Other  glucosides 
— Ouabain  or  Acocantherin  and  Acocanthin — are  found  in  Strophanthus 
glaber  and  in  Acocanthera  and  are  also  closely  related  to  strophanthin. 
Some  of  the  strophanthus  genus  contain  non-glucosidal  active  bodies. 
The  strophanthin  of  commerce  is  generally  derived  from  a  mixture  of 
different  species  and  varies  much  in  composition  and  toxicity. 

Scilla  maritima,  or  squills,  is  said  to  contain  Scillain,  a  glucoside,  very 
soluble  in  alcohol,  scarcely  so  in  water,  but  this  requires  further  in- 


THE  DIGITALIS  SERIES.  437 

vestigation.  Several  other  active  constituents  have  been  described  in 
squills,  but  none  of  them  have  been  actually  isolated,  and  they  may  be 
merely  impure  forms  of  scillain.  Saponin  bodies  are  also  present. 

HelLeborus  niger  contains  Helleborein,  a  glucoside,  which  is  very 
soluble  in  water,  and  resembles  digitalin  in  action,  and  Helleborin, 
which  is  insoluble  in  water  and  has  an  entirely  different  effect. 

Convallamarin  (obtained  from  Convallaria),  Adonldin  (Adonis),  Oleandrin, 
Neriin  and  Neriodorin  (Nerium),  Euonymin  (Euonymus),  Antiarin  (Antiaris), 
Thevetin  and  Cerberin  (Thevetia),  Cheiranthin  (Cheiranthus),  Coronillin  CCoro- 
nilla),  Tanghinin  (Tanghinia  venenifera),  and  Apocynein  (Apocynum),  are 
glucosides,  while  Apocynin  (Apocynum)  is  indifferent  and  Erythrophlceine 
(Erythrophlceum  guinense)  is  a  glucosidal  alkaloid. 

With  the  exception  of  the  last,  then,  the  members  of  this  series  which 
have  been  examined  hitherto  are  either  glucosides  or  indifferent  substances, 
containing  carbon,  hydrogen  and  oxygen,  but  no  nitrogen.  They  are  all 
liable  to  decompose  when  kept  long  in  watery  solutions,  and  especially  when 
heated  with  acids,  and  then  frequently  form  substances  which  no  longer  pos- 
sess the  digitalin  action,  but  are  rather  to.  be  classed  with  picrotoxin.  (See 
page  436.)  It  will  be  shown  later  that  even  digitalin  and  its  congeners  have 
this  picrotoxin  action  to  a  greater  or  lesser  degree,  and  it  seems  probable, 
therefore,  that  all  of  them  are  derivatives  of  some  common  nucleus,  which 
belongs  to  the  picrotoxin  series,  but  which  in  combination  assumes  a  new 
character  through  its  action  on  the  heart  and  vessels. 

Erythrophlceine  and  a  more  recently  isolated  alkaloid,  Muawine,  which 
resembles  it  in  most  respects,  split  off  a  molecule  of  sugar  when  they  are 
boiled  with  acids.  This  glucosidal  reaction  perhaps  indicates  that  they  are 
more  closely  related  to  the  other  members  of  the  series  than  would  appear 
at  first  sight. 

Action.  —  The  digitalis  series  possesses  a  local  and  a  general  action. 
The  Local  Effects  consist  in  primary  irritation,  followed  frequently 
by  paralysis  of  the  sensory  nerve  endings.  Thus  in  the  eye  a  small 
quantity  of  a  solution,  or  a  minute  particle  of  the  dry  poison  causes 
the  most  intense  pain,  redness  and  congestion  of  the  conjunctiva,  and  all 
the  symptoms  of  an  acute  inflammation.  On  the  tongue  the  bitter  taste 
is  followed  by  burning  pain  frequently,  and  if  the  powder  be  drawn 
into  the  nostrils  and  larynx,  marked  swelling  of  the  mucous  membrane, 
sneezing,  coughing  and  hoarseness  are  produced  in  many  persons.  They 
have  little  action  on  the  skin,  although  here  too  smarting  is  occasion- 
ally produced ;  but  when  injected  subcutaneously  many  of  them  cause 
marked  inflammation,  which  not  infrequently  ends  in  the  formation  of 
abscesses,  even  although  the  injection  has  been  absolutely  aseptic.  The 
same  irritant  action  is  produced  in  the  stomach  by  several  of  them, 
and,  in  fact,  by  all  of  them  when  taken  in  very  large  quantities  or  for 
long  periods.  This  irritant  action  is  not  equally  marked  throughout 
the  series,  however,  for  digitoxin  is  much  the  most  powerful  in  this 
respect,  while  digitalin  may  be  injected  subcutaneously  without  danger 
and  without  pain.  Their  local  irritant  action  explains  the  use  of  squills 
as  an  emetic,  and  of  euonymus  as  a  purgative.  The  local  anesthetic 
property  is  likewise  not  equally  developed  in  all  the  members  of  the 
series ;  several  of  them  (strophanthin,  ouabain,  erythrophlceine)  have 


438  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

been  suggested  as  local  anaesthetics  for  the  eye,  but  their  primary  irri- 
tant effect  precludes  their  use  for  this  purpose. 

After  absorption,  the  chief  symptoms  are  due  to  their  action  on  the 
central  nervous  system,  the  heart,  and  the  vessels,  more  especially  on 
the  two  last.  The  action  on  the  Central  Nervous  System  is  frequently 
ignored  or  attributed  to  the  changes  in  the  heart  as  a  secondary  effect, 
but  there  is  undoubtedly  a  stimulation  of  some  of  the  nerve  centres, 
quite  independent  of  the  action  on  the  heart  and  vessels.  This  stimu- 
lation, like  that  of  picrotoxin,  seems  almost  entirely  limited  to  the 
medulla  oblongata  in  many  cases.  In  the  frog  the  excitability  of  the 
reflexes  is  often  lowered  by  members  of  this  series,  probably  because 
of  the  intense  stimulation  of  the  medulla  oblongata ;  but  sometimes  a 
distinctly  increased  irritability  is  observed.  These  alterations  are  much 
greater  than  those  caused  by  the  interruption  of  the  circulation,  and 
are  therefore  independent  of  the  action  on  the  heart,  to  which  they  have 
been  erroneously  ascribed.  More  marked  symptoms  are  produced  in 
mammals,  however,  by  this  central  nervous  stimulation,  for  in  these 
vomiting  is  elicited  very  soon  after  the  injection  of  large  quantities, 
long  before  the  heart  is  very  seriously  affected,  and  this  is  undoubtedly 
due  to  action  on  the  medulla  oblongata.  To  the  same  cause  is  to  be 
attributed  the  rapid,  deep  respiratory  movements  and  convulsions, 
which  are  often  observed  in  the  later  stages  of  poisoning,  and  which 
are  evidently  not  due  to  cerebral  anaemia,  as  has  been  supposed,  for  the 
brain  at  this  stage  receives  quite  as  much  or  more  blood  than  it  nor- 
mally does.  Even  small  quantities,  such  as  are  used  therapeutically, 
cause  stimulation  of  certain  parts  of  the  central  nervous  system,  for  the 
activity  of  the  inhibitory  cardiac  centre  in  the  medulla  is  the  cause  of 
the  slowness  of  the  heart  which  is  seen  in  therapeutics  and  in  experi- 
ments on  mammals. 

The  central  nervous  system,  then,  undergoes  distinct  stimulation  un- 
der digitalis.  This  stimulation  by  small  quantities  seems  limited  to 
the  inhibitory  cardiac  and  the  vaso-constrictor  centres  in  the  medulla 
oblongata,  but  when  larger  doses  of  digitalis  and  its  allies  are  injected, 
other  parts  of  the  medullary  centres  become  stimulated,  and  vomiting, 
increased  respiration  and  eventually  general  convulsions  may  be  pro- 
duced. 

The  extent  to  which  the  members  of  this  series  act  as  stimulants  to 
the  nervous  centres  varies,  erythrophloeine  seeming  to  approach  more 
nearly  to  picrotoxin  than  the  others,  while  helleborein  is  among  the 
least  active,  but  as  yet  little  comparative  work  has  been  done  in  this 
direction. 

The  action  on  the  Heart  is  the  most  important  of  all,  and  is  what 
distinguishes  digitalis  and  its  allies  from  all  other  substances.  This 
action  has  been  studied  most  carefully  in  the  frog,  and  is  found  to  be 
due  to  an  alteration  in  the  cardiac  muscular  tissue.  On  exposing  the 
frog's  heart,  and  watching  its  movements  after  the  injection  of  digitalis^ 
the  muscular  action  can  generally  be  made  out  very  distinctly  (Fig.  37). 
The  heart  becomes  slower  in  rhythm,  and  contracts  to  smaller  dimensions 


THE  DIGITALIS  SERIES.  439 

in  systole,  while  it  does  not  dilate  so  fully  in  diastole.  The  ventricle 
is  therefore  whiter  during  systole  than  normally,  while  during  diastole 
it  does  not  seem  so  purple,  owing  to  its  containing  less  blood  at  each 
period.  The  slowing  can  be  seen  to  be  due  to  the  heart  remaining 
contracted  longer  than  usual,  while  the  dilatation  is  very  short  and 
imperfect.  Later  the  apex  of  the  ventricle  ceases  to  dilate  during 
diastole,  and  remains  quite  still  while  the  base  still  dilates  after  each 
auricular  systole.  Or  the  whole  ventricle  dilates  only  once  for  every 
two  contractions  of  the  auricle,  or  the  two  halves  of  the  ventricle  may 
contract  alternately  so  that  the  blood  is  thrown  from  one  side  to  the 
other.  Meanwhile  the  duration  of  systole  becomes  still  more  prolonged, 
and  the  extent  of  diastolic  dilation  diminishes  until  the  ventricle  finally 
ceases  to  contract,  remaining  in  a  position  of  extreme  systole  with  its 
cavity  obliterated.  The  auricles  come  to  a  standstill  also,  but  they 
are  unable  to  empty  themselves  into  the  contracted  ventricle  and  there- 
fore remain  distended  with  blood.  The  typical  action  of  digitalis  on  the 
muscle  of  the  frog's  heart,  then,  consists  in  a  tendency  to  increased 
and  prolonged  contraction,  and  diminished  and  shortened  diastole. 

In  some  cases  certain  other  features  appear  in  the  frog's  heart,  for  the 
slow  rhythm  may  be  accompanied  by  a  less  perfect  systole,  and  instead 
of  the  heart  ceasing  in  systole,  it  may  come  to  a  temporary  standstill  in 
a  state  of  extreme  diastolic  dilatation.  This  is  due  to  stimulation  of 

FIG.  37, 


D 


/  V  V 


Tracing  of  the  movement  of  the  frog's  ventricle  under  digitalis.  The  lever  forms  an  upward  stroke 
during  systole.  A,  normal  ;  £,  the  systole  is  somewhat  more  complete  and  is  very  prolonged,  and 
the  rhythm  is  correspondingly  slow.  "C,  the  ventricle  remains  in  systole  with  occasional  feeble  dias- 
tolic movements.  D,  the  diastoles  of  the  heart  have  almost  entirely  ceased.  A',  diagram  of  the  heart 
of  the  frog  in  its  normal  dimensions,  a,  auricle ;  v,  ventricle  with  the  aortic  bulb  rising  from  it. 
The  dotted  line  in  the  ventricle  represents  the  outline  in  systole,  the  continuous  line  the  outline  in 
diastole.  D',  outline  of  the  heart  in  the  standstill  after  digitalis.  The  ventricle  v  is  very  much  con- 
tracted, the  auricle  a  distended  with  blood. 

the  vagus  centre  in  the  medulla,  and  must  be  carefully  distinguished 
from  the  action  on  the  cardiac  muscle.  Not  infrequently  the  two  forms 
occur  in  combination,  or  the  symptoms  of  inhibitory  action  precede 
those  of  the  true  cardiac  change. 


440 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


The  amount  of  blood  expelled  by  the  heart  varies  according  to  the 
degree  to  which  each  of  these  factors  comes  into  play.  If  the  dilata- 
tion in  diastole  is  unchanged  or  increased,  while  the  contraction  is 
greater  than  normal,  the  amount  of  blood  expelled  by  each  beat  is  of 
course  increased,  but  as  the  dilatation  becomes  less,  the  amount  ex- 
pelled diminishes  until  it  reaches  zero.  Even  though  the  amount  of 
blood  expelled  by  each  beat  is  increased,  one  finds  not  infrequently 
that  the  total  output  per  minute  is  diminished  because  the  rhythm  is 
so  much  slower  than  usual. 

The  irritability  of  the  heart  muscle  is  also  found  to  be  considerably 
increased  by  digitalis.  Thus  if  the  ventricle  of  the  unpoisoned  frog's 
heart  be  excised,  and  salt  solution  be  led  through  it,  it  ceases  to  beat 
after  some  time.  If,  however,  a  small  quantity  of  digitalis  be  added 
to  the  salt  solution,  rhythmical  contractions  are  often  induced  and  the 
heart  eventually  passes  into  systolic  standstill.  This  increased  irri- 
tability may  explain  a  temporary  acceleration  of  the  cardiac  rhythm, 
which  is  occasionally  seen  in  frogs  and  in  other  cold-blooded  animals. 

The  nature  of  the  action  on  the  cardiac  muscle  has  been  a  good  deal 
discussed.  Schmiedeberg  brought  forward  the  theory  that  it  was 
mainly  an  increase  in  the  elasticity  of  the  heart  muscle,  but  this  has 
been  disputed  by  Roy,  who  showed  that  it  was  not  sufficient  to  explain 
the  phenomena.  With  the  present  knowledge  of  the  molecular  changes 
which  occur  in  the  heart,  it  is  impossible  to  proceed  beyond  the  state- 
ment that  the  muscle  tone  is  increased,  and  that  thereby  the  relaxation 


FIG.   38. 


N' 


N 


Tracings  of  the  ventricular  contractions  under  digitalis  in  experiments  on  two  dogs.  N,  N',  normal 
contractions.  D,  D1 ,  contractions  under  digitalis.  The  levers  move  upwards  during  systole.  In  D 
the  rhythm  is  slower  and  the  movements  extend  further  upwards  and  downwards  than  in  N,  i.  e.,  the 
contractions  are  more  complete  and  the  dilatation  during  diastole  is  greater.  In  D'  the  rhythm  is 
slower,  and  the  tracing  extends  further  upwards  than  in  N',  but  reaches  almost  the  same  point  below, 
*'.  «.,  the  contraction  is  stronger,  but  the  dilatation  is  scarcely  changed.  Contrast  the  effects  of  inhibi- 
tion alone  in  Figs.  27  and  29  (pp.  289  and  319). 

of  the  muscle  is  rendered  less  perfect  and  the  contraction  more  complete 
and  prolonged.  The  inhibitory  action  of  the  vagus,  on  the  contrary, 
tends  to  render  the  tone  less  complete,  and  to  produce  less  complete 
contraction  and  more  complete  diastole.  The  direct  effects  of  digitalin 
on  the  cardiac  muscle  of  the  frog  are  therefore  diametrically  opposed  to 
those  of  inhibitory  activity. 

The  hearts  of  some  invertebrates,  such  as  of  the  snail,  are  said  to 
undergo  changes  similar  to  those  described  in  the  frog's  heart,  while  the 
crustaceans  seem  to  be  entirely  unaffected  by  digitalis. 


THE  DIGITALIS  SERIES. 


441 


FIG.  39. 


The  action  on  the  frog's  heart  is  of  great  interest,  because  the  changes 
produced  by  this  series  on  the  mammalian  heart  partake  largely  of  the 
same  character.  The  inhibitory  and  the  muscular  actions  are  again 
opposed  to  each  other,  but  here  the  inhibitory  is  almost  invariably 
present  to  a  greater  or  less  degree.  The  action  of  digitalis  and  its  allies 
on  the  mammalian  heart  may  be  divided  into  three  stages,  of  which  the 
first  and  the  third  are  always  developed  when  sufficient  quantities  are 
administered.  The  second  stage  may  be  absent  in  certain  circum- 
stances, but  is  also  generally  present  in  poisoning. 

In  the  first  or  therapeutic  stage  of  the  action  of  this  series,  the  rhythm 
of  the  heart  is  changed,  and  the  extent  of  contraction  and  relaxation 
of  the  ventricle  and  auricle  undergo  certain  modifications  (Fig.  38). 
The  rhythm  of  the  heart  is  distinctly  slower  than  before  giving  the 
drug,  for  the  inhibitory  apparatus  is  set  in  activity,  and  the  slowing  is 
accordingly  due  to  a  prolongation  of  the  pause  in  diastole.  The  ventri- 
cles contract  to  a  smaller  size,  that  is,  they  empty  themselves  much  more 
completely  than  they  normally  do.  It  is  now  universally  recognized 
that  the  normal  ventricle  does  not  empty  itself  completely ;  that  even 
at  the  end  of  its  systole  there 
still  remains  some  blood  in 
its  interior.  After  the  action 
of  this  group  has  begun,  how- 
ever, the  blood  remaining  at 
the  end  of  systole  is  much 
less  than  before.  This  in- 
creased contraction  is,  like 
that  in  the  frog's  heart,  due 
to  action  on  the  cardiac  mus- 
cle, and  leads  to  an  augmented 
pressure  in  the  ventricle  dur- 
ing systole.  The  papillary 
muscles  undergo  the  same 
changes  as  the  rest  of  the 
ventricular  wall,  contracting 
more  strongly  and  more  com- 
pletely than  before  the  ad- 
ministration of  the  drug. 

The  relaxation  of  the  ven- 
tricle is  found  to  vary  in  dif- 
ferent conditions.  If  the 
heart  is  weak  and  dilated, 
digitalis  and  its  allies  tend  to 
lessen  this  dilatation,  that  is, 
the  relaxation  of  the  ventricle 
during  diastole  is  less  than 
before  the  administration  of  the  drug.  (See  Fig.  39.)  If,  however, 
the  heart  is  normal,  or  does  not  dilate  much  during  diastole,  digitalis 
increases  the  relaxation.  (Fig.  38,  D.)  The  variation  in  the  degree 


B  A 

Tracings  of  the  movements  of  the  ventricle  (lower) 
and  auricle  (upper)  under  digitalis.  During  systole  the 
levers  make  an  upstroke.  In  this  experiment  the  in- 
hibitory terminations  had  heen  paralyzed,  so  that  only 
the  muscular  action  is  developed.  A,  normal ;  B,  after 
digitalis.  The  rhythm  of  the  heart  is  slightly  acceler- 
ated in  B,  and  the  levers  extend  further  upwards,  indi- 
cating a  more  perfect  systole  in  both  auricle  and  ven- 
tricle. The  ventricular  lever  does  not  reach  so  far 
downwards  in  B,  i.  e.,  the  ventricular  diastole  is  less 
complete. 


442 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


of  dilatation  of  the  ventricle  depends  upon  the  opposing  factors — the 
inhibition  and  the  muscular  action.  If  the  inhibition  be  the  stronger, 
the  ventricle  relaxes  more  completely  than  before,  for  vagus  stimula- 
tion always  tends  to  increase  the  relaxation  of  the  heart.  If,  on 
the  other  hand,  the  muscular  action  predominates,  the  relaxation  is 
lessened,  for  here,  as  in  the  frog's  heart,  this  series  tends  to  lessen 
the  extent  of  relaxation.  In  the  normal  heart  the  application  of  one 
of  this  series  causes,  as  a  general  rule,  an  increase  in  the  extent  of 
relaxation. 

It  must  be  added  that  the  inhibition  is  due  in  part  to  stimulation  of 
the  intra-cardiac  inhibitory  apparatus,  but  mainly  to  the  stimulation 
of  the  vagus  centre  in  the  medulla.  This  is  shown  by  cutting  the  vagi 
before  the  injection,  for  the  slowing  is  then  much  less  than  when  the 
vagi  are  intact,  or  may  be  entirely  absent. 

If,  then,  the  ventricles  contain  more  blood  at  the  beginning  of  sys- 
tole, i.  e.j  are  more  relaxed  than  usual,  and  if  the  quantity  remaining 
at  the  end  of  systole  is  less  than  normal,  the  heart  must  expel  much 
more  blood  at  each  ventricular  contraction  than  it  does  normally.  (See 

Fig.  40.)    Even  though  the 

FIG.  40.  amount  of  blood  at  the  be- 

ginning of  systole  is  un- 
changed or  slightly  dimin- 
ished (lessened  dilatation), 
as  occasionally  happens,  the 
amount  expelled  is  increased 
because  the  ventricles  con- 
tract more  completely.  If 
the  number  of  beats  per 
minute  remained  the  same, 
therefore,  the  amount  of 
blood  expelled  (or  the  out- 
put) would  be  much  increas- 
ed ;  but  the  rhythm  is  slower 
than  normal,  and  although 
each  beat  propels  a  larger 
amount  of  blood  into  the 

A  (normal)  and  in  .Bit  can  also  rise  higher.     The  output  aorta  and  pulmonary  artery 
of  each  stroke  is  represented  by  the  shaded  part  of  the  cyl-  "  .     .    J  .     J 

inder  and  is  greatest  in  B,  in  which  more  fluid  is  present  than  normally,  it  IS  not  im- 
at  the  beginning  of  the  stroke  (diastole)  and  less  at  the  end  ..  .       ,         *y 

of  the  stroke  (systole)  than  in  A.    It  is  also  greater  in  C,  possible  that  the  OUtpUt  may 

in  which  the  same  amount  of  fluid  is  present  at  the  hegin-  {       -,          ,1  -i     p         j.u      J 

ning  of  the  stroke  (diastole)  as  in  A,  but  less  is  present  at  DC  l6SS  than   foetore  the  drug 
the  end  (systole).    If  the  pistons  make  the  same  number  of  orlrvn'tiicfovorl         Tn     tliP 

strokes  per  minute  in  A,  B  and  C,  the  amount  of  fluid  Was    administered.        in    1116 

SKhwoTwK^icte!  B  and  least  in  A>  which  repre~   therapeutic    use    of    these 

drugs   the    slowing    is    not 

great  enough  to  counterbalance  the  in  creased  output  per  beat,  and  a  larger 
amount  of  blood  is  therefore  driven  into  the  aorta  and  pulmonary  artery. 
The  more  complete  contraction  of  the  ventricle  also  causes  a  higher 
pressure  in  its  interior  than  before,  and  the  blood  is  therefore  expelled 
into  the  vessels  under  greater  pressure  than  normally. 


THE  DIGITALIS  SERIES.  443 

The  changes  in  the  ventricle,  then,  are  due  to  inhibitory  activity  and 
to  direct  cardiac  action,  the  first  tending  to  lessen  the  number  of  beats, 
to  increase  the  relaxation  of  the  fibres  and  to  weaken  the  systole,  and 
thus  to  diminish  the  output  and  efficiency  of  the  heart ;  the  second 
tending  to  strengthen  the  systole  and  thus  to  augment  the  output,  while 
also  limiting  the  dilatation,  which  may  increase  or  lessen  the  efficiency 
of  the  heart  according  to  circumstances. 

In  the  auricles  the  same  two  agencies  are  found  in  opposition,  the 
inhibitory  stimulation  and  the  muscular  actions.  Stimulation  of  the 
inhibitory  nerves  causes  in  the  auricle  more  or  less  increase  in  the  dila- 
tation, while  it  lessens  the  contraction  considerably,  and  in  fact  may 
prevent  it  entirely.  The  muscular  action  of  this  series  is  the  same 
here  as  in  the  ventricle,  causing  a  tendency  towards  more  complete 
systole  and  less  complete  relaxation.  After  small  quantities,  such  as 
are  used  in  medicine,  the  rhythm  of  the  auricle  is  slow,  like  that  of 
the  ventricle,  owing  to  the  inhibition  ;  the  relaxation  is  little  changed, 
but,  owing  to  the  muscular  action,  the  contraction  is  more  complete. 
In  but  slightly  larger  quantities,  however,  the  inhibitory  action  causes 
a  less  complete  contraction,  so  that  the  work  done  by  the  auricle  is 
actually  less  than  before  the  injection. 

The  rhythm  of  the  different  parts  of  the  heart  is  exactly  the  same 
during  this  stage,  and  the  changes  seen  in  the  right  auricle  and  ventri- 
cle correspond  to  those  in  the  left. 

Not  infrequently  a  previously  irregular  heart  becomes  more  regular 
under  the  influence  of  small  doses  of  digitalis,  and  this  has  generally 
been  regarded  as  the  result  of  the  inhibitory  action,  which  lessens  the 
irritability  of  the  heart  and  thus  reduces  the  tendency  to  premature 
contractions.  But  several  investigators  have  recently  shown  that  the 
same  regularizing  action  is  exercised  by  digitalis  in  the  excised  heart, 
when  there  could  be  no  question  of  inhibition ;  they  therefore  ascribe 
this  result  to  some  obscure  changes  induced  by  the  muscular  action  of 
this  series  (Gottlieb  and  Magnus,  Brandenburg). 

If  larger  quantities  be  injected,  either  the  inhibitory  or  the  muscular 
action  may  become  markedly  increased,  and  the  appearance  of  the 
heart  varies  according  to  which  of  these  predominates.  It  must  be 
distinctly  understood  that  the  following  symptoms  betoken  a  grave 
condition  of  poisoning  and  are  not  met  with  in  the  therapeutic  use  of 
the  series. 

In  the  second  stage,  the  symptoms  are  due  to  excessive  inhibitory 
activity,  while  the  direct  cardiac  action  is  less  developed.  The 
rhythm  of  the  ventricle,  and  consequently  of  the  pulse,  is  very  slow 
and  irregular,  as  is  always  the  case  when  the  inhibitory  apparatus  is 
strongly  stimulated  (see  Fig.  27,  p.  289).  During  diastole  the  ven- 
tricle dilates  more  completely  than  usual,  while  its  systole  varies  in 
strength.  If  the  muscular  action  is  well  developed,  it  continues  to 
empty  itself  more  completely  than  usual,  but  very  often  the  inhibition 
is  so  powerful  that  the  muscular  action  is  entirely  concealed  and  the 
svstole  is  weaker  and  more  blood  remains  at  the  end  of  the  contrac- 


444 


ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 


tion  than  before  the  drug  was  administered.  As  a  general  rule,  how- 
ever, each  beat  expels  more  blood  than  normally,  because  the  heart  is 
engorged  before  the  systole  begins  ;  but  the  rhythm  is  so  slow  that 
the, output  per  minute  and  the  efficiency  of  the  heart  as  a  pump  is  less 
than  usual.  This  is  the  feature  which  differentiates  the  first  from  the 
second  stage,  in  which  the  same  factors  are  present ;  in  the  first  stage 
the  efficiency  of  the  heart,  i.  e.,  the  amount  of  blood  expelled  per 
minute,  is  greater,  in  the  second  stage  less  than  before  the  administra- 
tion of  the  drug. 

Not  infrequently  the  auricle  and  ventricle  beat  in  different  rhythms, 
the  ventricle  developing  a  spontaneous  rhythm  which  may  be  either 
faster  or  slower  than  that  of  the  auricle.  This  is  apparently  due  to 
the  inhibitory  action,  which  blocks  the  passage  of  impulses  from  the 
auricle  to  the  ventricle,  although  the  effect  of  the  drug  in  increasing 
the  irritability  of  the  cardiac  muscle  may  contribute  to  it  by  facilitat- 
ing the  development  of  the  spontaneous  ventricular  rhythm. 

The  auricular  contractions  are  much  weaker  than  in  the  first  stage, 
and  even  than  in  the  normal  heart,  and  may  cease  altogether  for 
some  time,  while  the  chambers  do  not  tend  to  dilate  further  as  a 
general  rule. 

Although  the  rhythms  of  the  auricle  and  ventricle  may  differ  at 
this  stage,  the  two  ventricles  always  beat  in  unison,  and  the  changes 
in  the  strength  of  their  contraction  and  in  the  extent  of  the  relaxation 
are  similar. 

This  stage  of  excessive  inhibition  is  not  observed  in  every  case  of 
poisoning  in  animals,  nor  probably  in  man,  although  in  the  recorded 
instances  of  poisoning  with  the  members  of  this  series,  it  seems  to  have 
been  present,  as  the  pulse  is  said  to  have  been  very  slow  and  irregular. 

FIG.  41. 


Tracing  of  the  auricular  (upper)  and  ventricular  movements  (lower)  under  digitalis,  as  the  first 
stage  passes  into  the  second.  During  systole  the  levers  move  upwards,  during  diastole  downwards. 
The  rhythm  of  the  two  chambers  is  at  first  the  same,  but  soon  changes,  the  auricle  maintaining  its 
rapid  beat  while  the  ventricle  becomes  slow  and  irregular.  At  the  end  of  the  tracing  the  ventricle 
again  becomes  rapid,  while  the  auricle  becomes  slow.  The  strength  of  the  contractions  and  the  extens 
of  relaxation  of  the  ventricle  muscle  remain  little  altered,  while  the  auricle  rapidly  weakens  in 
strength,  but  improves  again  at  the  end  of  the  tracing. 

Therapeutic  doses  of  these  drugs  never  induce  irregularity  in  them- 
selves, though  the  pulse  is  often  irregular  from  disease  in  the  cases  in 
which  they  are  prescribed.  When  in  their  therapeutic  use  irregular- 


THE  DIGITALIS  SERIES. 


445 


ity  arises  from  their  effects,  the  physician  is  inducing  the  second  stage 
of  poisoning,  in  which  the  efficiency  of  the  heart  is  less  than  it  would 
be  without  the  drug,  and  the  dose  ought  to  be  reduced  at  once.  If 
the  inhibitory  mechanism  is  weak  or  is  paralyzed  by  the  preliminary 
injection  of  such  drugs  as  atropine,  the  second  stage  is  entirely  absent. 

When  very  large  quantities  of  any  of  this  series  are  injected,  the 
third  stage  sets  in.  It  is  preceded  by  the  first  for  a  short  time,  gener- 
ally by  both  first  and  second.  In  this  stage  the  ventricular  rhythm 
becomes  very  much  accelerated,  often  beyond  the  normal,  and  even 
beyond  that  seen  after  paralysis  of  the  inhibitory  nerves.  This  ac- 
celeration has  often  been  supposed  to  be  produced  by  paralysis  of  the 
vagus,  but  this  is  not  the  correct  explanation,  for  stimulation  of  this 
nerve  sometimes  still  slows  the  heart  and  always  causes  dilatation 
The  acceleration  is  really  due  to  the  drug  increasing  the  irritability  of 
the  heart  muscle  to  such  an  extent  that  the  inhibitory  apparatus  is  no 
longer  able  to  hold  it  in  check. 

The  auricles  also  undergo  the  same  changes.     They  begin  to  accel- 
erate their  rhythm,  and  if  the  second  stage  has  not  developed,  they 
continue  in  the  same  rhythm  as  the  ventricle.     If,  however,  the  ven- 
tricular rhythm  has  been  independent  of  the  auricular  in  the  second 
stage,  the  auricles  are  often  later  in  being  accelerated  than  the  ven- 
tricles, because  the  inhibitory  nerves  act  more  strongly  on  them.    The 
difference  in  rhythm  of  the  two  divisions  leads  to  a  very  characteristic 
periodic  variation  in  the  strength  of  the  contractions  of  both  auricle 
and  ventricle.     This  auriculo-ventricular  arhythmia  may  continue  for 
some  time,  but  farther  irregularities  soon  present  themselves.     At  in- 
tervals, asystole  of  either 

ventricle  or    auricle  ap-  FIG.  42. 

pears,  that  -is,  two  con-        *  '  '  '  '  '  '  <  >  >   •  >  <  •  i  i  .  .  .  .  .  .  .  . 

tractions  follow  so  rapid- 

ly   on    each    other,    that  n   • 

the  chamber  has  no  time 

to   dilate    fully    between  1  ft    H 

them  and  no  blood  is  ex- 

pelled by  the  second  one. 

These   asystolic  contrac- 

tions   become   more   nu- 

merous,  and    soon    form 

groups  of  two  or  three, 

separated  by  other  groups 

of  ordinary  contractions.      '  '  '    j      U  '  '  "  I 

The       rhythm        becomes  Tracing  Of  the  ventricular  movements  in  the  last  stage  of 

more     and      more      raDid  digitalis  poisoning.     The  lever  moves  upwards  in  systole.     The 

1.1          n                 n  •            '  characteristic  feature  is  the  extreme  irregularity,  no  two  con- 

ana  Other  lOrniS  Ol  irreg-  tractions  resembling  each  other  in  form  or  streng'th. 

ularity  appear,  which  it 

is  impossible  to  describe  here.  Eventually  the  auricle  generally  passes 
into  fibrillary  contractions  while  the  rhythm  of  the  ventricle  continues 
to  increase,  and  the  force  of  its  contractions  and  the  output  of  each 


446  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

beat  decrease.  The  ventricle  finally  passes  into  fibrillary  contractions 
also,  and  the  circulation  is  arrested,  after  which  the  heart  dilates  to  an 
extreme  degree. 

All  the  features  of  the  third  stage  are  due  to  the  poisons  increasing 
the  irritability  of  the  heart  muscle.  This  leads  to  acceleration  of  the 
beat,  and,  eventually,  through  the  muscle  of  one  pair  of  chambers 
being  acted  on  more  than  that  of  the  other,  to  arhythmia.  The  asys- 
tolic  contractions  are  evidently  of  the  same  origin,  and  the  final  delir- 
ium is  also  to  be  ascribed  to  this  action.  Almost  all  the  characteristic 
features  of  this  stage  may  be  imitated  in  the  normal,  unpoisoned  heart 
by  stimulating  the  different  chambers  by  electric  shocks  ;  the  impulses 
which  in  the  poisoned  heart  arise  from  its  own  excessive  irritability 
are  here  given  by  the  artificial  stimuli,  but  the  effect  is  the  same. 

The  output  of  the  heart  continues  much  augmented  during  the  first 
part  of  the  third  stage,  but,  as  the  irregularity  of  the  ventricles  in- 
creases, and  the  asystolic  contractions  become  more  numerous,  it  be- 
comes less  and  eventually  falls  to  zero  when  the  heart  passes  into  de- 
lirium. Throughout  the  whole  course  of  the  intoxication  the  ventricles 
beat  in  unison,  no  interventricular  arhythmia,  such  as  has  been  de- 
scribed by  some  authors,  being  noticeable  at  any  stage.-  The  two 
auricles  often  differ  somewhat  in  their  rhythm  in  the  third  stage,  and 
the  rhythm  of  the  ventricles  may,  as  has  been  stated,  be  entirely  dif- 
ferent from  that  of  the  auricles  in  either  the  second  or  third  stage. 

The  effects  of  digitalis  on  the  mammalian  heart  therefore  resemble 
in  general  those  observed  in  the  frog's.  The  contraction  is  not  pro- 
longed, however,  as  it  is  in  the  latter,  and  the  inhibitory  mechanism 
plays  a  more  important  role.  The  irregular  stage  evidently  corre- 
sponds in  each,  and  the  final  delirium  cord  is  in  the  mammal  represents 
the  continued  contraction  in  the  frog,  the  mammalian  heart  not  being 
capable  of  a  continued  systole.  The  heart  in  mammals  is  generally 
found  in  a  condition  of  diastole  in  cases  of  fatal  digitalis  poisoning, 
and  this  has  been  supposed  to  indicate  a  fundamental  difference  in  the 
action  of  digitalis  on  the  amphibian  and  mammalian  heart.  The  dila- 
tation is  not,  however,  a  direct  result  of  the  digitalis  but  is  probably 
induced  by  the  poisons  formed  in  the  heart  by  its  own  activity.  When 
the  mammalian  heart  is  excised  and  blood  containing  digitalis  is  per- 
fused through  the  coronary  vessels,  complete  systolic  standstill  of  the 
ventricle  resembling  that  seen  in  the  frog  is  often  the  final  outcome. 

The  Peripheral  Vessels  are  affected  in  several  ways  by  the  members 
of  this  series.  The  increased  output  of  the  heart  in  the  therapeutic 
stage  augments  the  pressure  in  their  interior,  and  it  seems  not  unlikely 
that  the  vaso-motor  centre  is  stimulated  and  that  this  causes  a  con- 
traction of  the  arterial  walls.  But  in  addition  to  these  effects,  the 
muscular ^wall  of  the  arterioles  is  constricted  by  a  direct  action  of  the 
glucosides  and  the  resistance  to  the  flow  of  blood  from  the  arteries  to 
the  veins  is  increased,  which  further  raises  the  tension  in  the  aorta 
and  larger  arteries.  It  seems  likely  that  all  the  members  of  the  group 
do  not  act  equally  at  all  three  points,  but  very  little  is  known  defi- 


THE  DIGITALIS  SERIES. 


447 


nitely  on  the  subject  except  that  digitoxin  acts  more  powerfully  ou  the 
vessels  than  some  of  the  others,  and  that  erythrophloeine  acts  more  on 
the  medulla  and  less  on  the  heart  than  any  other  glucoside  hitherto 
examined. 

All  the  digitalis  bodies  then  increase  the  arterial  blood-pressure 
partly  through  changes  in  the  heart,  and  partly  through  contraction  01 
the  vascular  walls.  There  is  on  the  one  side  an  unusually  large 
amount  of  blood  expelled  by  the  heart,  on  the  other,  unusual  resist- 
ance to  its  passage  out  of  the  arteries.  And  this  appears  to  be  the 
final  result  when  digitoxin  is  injected.  .But  when  strophanthin,  digi- 
talin  or  convallamarin  is  used,  a  further  complication  arises,  for  these 
Tiave  a  somewhat  less  marked  vascular  action,  and  though  the  vessels 
of  the !_  abdominal  .organs  are  contracted  in  the~same  way  as  by  digi- 

FIG.  43. 


Leg 


iilMWiW^^ 


Tracings  of  the  blood-pressure  and  the  volume  of  the  leg  and  of  the  spleen  of  the  dog  under  stro- 
phanthus.  The  volume  of  the  leg  increases  with  the  blood-pressure,  i.  e.,  the  vessels  of  the  leg  are 
dilated  ;  that  of  the  spleen  diminishes,  i.  e.,  the  vessels  are  contracted  ;  10  mg.  of  strophanthus  were 
injected  intravenously  at  a,  followed  by  5  nig.  at  b.  (GOTTLIEB  and  MAGNUS.) 

toxin^ those  of  the  extremities  dilate.  This  dilatation  is  partly  owing 
to  the  increased  pressure  in  the  interior  overcoming  the  contraction  of 
the  walls,  but  is  mainly  tcL.fee .  ascribed  to  a  reflex  stimulation  of  the 
_vaso-dilator  centre  induced  by  the  contraction  of  the  abdominal  ves- 
sels. The  brain  vessels  react  in  the  same  way  as  those  of  the  limbs, 
digitoxin  contracting  them,  while  under  strophanthin  they  are  little 
aifected.  The  result  is  that  while  the  outflow  from  all  the  vessel's  is 
retarded  by  digitoxin,  the  blood  current  in  the  splanchnic  area  alone 
is  slower  under  strophanthin,  while  that  in  the  limbs  and  brain  is 
actually  accelerated.  The  rate  of  flow  through  the  qpronary  vessels 
of  the  heart  under  the  members  of  this  series  has  been  investigated  by 
Loeb,  who  finds  that  digitoxin  contracts  these  vessels  and  retards  the 
blood  supply  of  the  heart,  while  s^oj^anthin_a^  have  ittle 

influence  on  them. 


448  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

It  follows  that  under  all  of  the  series  the  blood  tends  to  accumulate 
on  the  arterial  side  at  the  expense  of  the  venous,  for  more  blood  is 
pumped  into  the  arteries  and  it  has  greater  difficulty  in  escaping.  But 
while  under  digitoxin  the  different  regions  of  the  body  appear  to  be 
equally  affected,  strophanthin,  digitalin  and  convallamarin  not  only 
tend  to  accumulate  the  blood  on  the  arterial  side,  but  divert  it  from 
the  internal  organs  to  the  limbs. 

When  the  extreme  slowing  of  the  second  stage  appears,  the  output 
of  the  heart  is  reduced,  and  the  pressure  in  the  aorta  and  the  velocity 
of  the  blood  may  become  subnormal  (Fig.  44).  When  the  acceleration 
of  the  third  stage  follows,  the  output  is  again  augmented  and  may  be 
greater  than  ever  ;  the  blood-pressure  and  velocity  increase,  but  the  heart 
soon  becomes  irregular  in  the  force  of  its  contractions,  the  output  varies 

FIG,  44, 

/l/WWWWVWWl 


WV1MA%1/1 


ABODE 

Blood-pressure  tracing  under  digitalis.  A,  normal  ;  B,  therapeutic  stage;  C,  excessive  inhibition 
causing  a  low  blood-pressure  from  lessened  output  of  the  heart.  D,  excessive  inhibition  with  some 
irregularity  in  rhythm.  E,  third  stage  of  irregularity,  during  which  the  blood-pressure  rises  again 
from  the  increased  output  of  the  heart  and  the  further  contraction  of  the  vessels. 

from  second  to  second,  and  the  pressure  and  velocity  in  the  aorta  fall 
slowly.  The  blood-pressure  tracing  shows  the  irregularity  of  the  heart 
more  or  less  accurately,  but  must  not  be  taken  to  indicate  at  all  the 
real  condition  of  that  organ,  as  the  constriction  of  the  arterioles  varies 
at  different  times.  Eventually  the  pressure  falls  to  zero,  when  the 
heart  ceases. 

In  the  pulmonary  circulation  the  pressure  is  not  raised  by  some  of 
the  series,  such  as  strophanthin  and  helleborein,  while  after  digitalis  a 
rise  in  the  pressure  in  the  pulmonary  artery  is  sometimes  seen.  Yet 
all  of  them  increase  the  output  of  the  right  ventricle.  The  explana- 
tion of  this  paradox  probably  is  that  the  pulmonary  vessels  can  con- 
tain not  only  the  ordinary  supply  of  blood,  but  also  an  increased 
volume  without  offering  any  great  resistance.  In  the  later  stages  the 
pulmonary  circulation  presents  irregularities  similar  to  those  of  the 
systemic. 


THE  DIGITALIS  SERIES. 


449 


Action  on  the  Renal  Secretion.  When  digitalis  was  first  introduced 
to  the  notice  of  the  medical  profession  by  Withering  its  action  on  the 
heart  was  not  appreciated.  Withering  used  it  only  to  remove  accumu- 
lations of  fluid  from  the  body,  which  it  accomplished  by  increasing  the 
secretion  of  urine.  This  observation  of  Withering  was  soon  confirmed 
by  further  experience  in  the  use  of  this  drug,  but  it  was  long  dis- 
puted whether  this  diuretic  action  occurred  in  health,  or  whether  it 
was  not  confined  to  cases  in  which  pathological  accumulations  of  fluid 
were  present.  Digitalis,  however,  as  is  now  conceded  by  almost 
everyone,  causes  some  increase  in  the  quantity  of  urine  secreted  by  the 
normal  animal,  although  this  is  small  compared  with  that  in  cases  of 
dropsy.  The  fluid  of  the  urine  is  much  more  largely  augmented  than 
the  solids,  which  may  remain  unchanged.  The  cause  of  this  increase 


FIG.   45. 


A    B    D 


D 


D" 


Diagram  representing  the  secretion  of  urine  in  a  rabbit  under  digitalis.  Each  rectangle  represents 
the  amount  of  urine  secreted  in  ten  minutes.  A  and  B,  normal  secretion.  In  the  next  ten  minutes 
a  small  dose  of  digitalis  D  was  injected  intravenously  and  a  rapid  increase  in  the  secretion  followed. 
At  D'  and  D"  further  injections  were  made,  each  being  succeeded  by  a  considerably  augmented 
now  of  urine.  The  dotted  line  represents  the  average  blood-pressure  at  each  period.  It  will  be  ob- 
served that  each  injection  is  followed  by  some  increase  in  the  arterial  tension.  Contrast  Fig.  23  (p. 
250)  as  to  the  amount  of  the  secretion,  and  also  as  to  the  behavior  of  the  blood-pressure. 

in  the  renal  secretion  is  not  generally  believed  to  be  a  direct  action  on 
the  secretory  mechanism,  such  as  is  met  with  under  caffeine ;  on  the 
contrary,  the  kidneys  themselves  are  supposed  to  be  acted  on  only  in- 
directly through  the  changes  in  the  circulation.  The  renal  vessels  are 
contracted  by  the  members  of  this  series  in  the  same  way  as  the  vessels 
of  the  other  abdominal  organs  (Gottlieb  and  Magnus),  and  this  might  be 
expected  to  lessen  the  secretion  of  urine,  for  other  agencies  which  con- 
tract the  renal  vessels  have  this  effect.  The  diuresis  induced  by  digi- 
talis-must accordingly  be  ascribed  to  the  cardiac  changes  and  not  to 
the  vaso-constrictor  action.  It  may  be  supposed  that  the  accumulation 
of  the  blood  in  the  arteries  and  the  consequent  fall  of  the  venous  pres- 
sure, which  has  been  shown  to  occur,  lead  to  an  augmented  flow  of  the 
lymph  into  the  blood  vessels,  and  that  the  blood  is  thus  diluted  and 

29 


450  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

the  kidneys  therefore  incited  to  abnormal  activity,  while  at  the  same 
time  their  nutrition  is  improved  ;  and  in  addition,  the  increased  pressure 
in  the  glomerulus  must  accelerate  the  filtration  through  the  capsule. 
It  is  possible,  also,  that  at  any  rate  some  of  the  members  of  this  series 
act  as  slight  irritants  to  the  renal  epithelium.  The  appearance  of  blood 
and  albumin  in  the  urine  of  animals  after  large  doses  of  squills  and 
digitalis  certainly  indicates  some  local  action  quite  apart  from  the  cir- 
culatory changes. 

The  changes  in  the  circulation  in  man  can  be  followed  only  imper- 
fectly. The  heart  rhythm  is  very  distinctly  slower,  and  the  apex  beat 
is  much  stronger  than  before  the  administration  of  the  drug  ;  the 
pulse  is  slower  and  stronger  and  the  artery  feels  more  tense.  It  must  be 
added  that  the  strength  of  the  pulse  is  not  to  be  regarded  as  a  gauge 
of  the  changes  in  the  cardiac  muscle,  for  it  is  due  not  only  to  the  in- 
creased strength  of  the  cardiac  contraction  but  also  to  its  slow  rhythm. 
When  the  heart  is  beating  rapidly,  the  arteries  have  no  time  to  empty 
themselves  completely,  and  the  pulse  is  small,  while  on  the  other 
hand,  when  digitalis  slows  the  heart,  the  arteries  have  time  to  empty 
their  contents  into  the  capillaries  before  the  next  contraction  occurs, 
the  walls  therefore  become  more  flaccid,  and  a  new  wave  of  blood 
causes  a  more  distinct  impulse.  In  some  cases  of  fever  the  vagus 
seems  to  have  less  control  over  the  heart  than  usual,  and  after  digi- 
talis there  is  no  very  marked  slowing,  although  the  action  on  the  car- 
diac muscle  may  be  fully  developed.  The  pulse  is  harder  owing  to 
the  increased  blood-pressure,  but  it  is  not  much  slower,  and  the  im- 
pulse does  not  seem  stronger  than  before.  If  the  physician,  judging 
from  the  pulse  that  the  drug  has  been  given  in  too  small  quantities, 
prescribes  larger  doses,  the  eifects  on  the  heart  may  be  disastrous,  as 
the  third  stage  of  irregularity  and  less  perfect  action  of  the  heart  may 
be  induced.  In  those  cases  in  which  this  series  seems  to  have  no  action 
on  the  pulse,  the  heart  and  the  general  condition  of  the  circulation  must 
be  very  carefully  examined  before  larger  quantities  are  prescribed. 
If,  for  example,  the  urine  be  found  increased,  or  the  oedema  is  less 
marked  than  before,  or  the  breathlessness  and  the  dyspnoea  have  dis- 
appeared, the  drug  is  fulfilling  its  chief  purpose,  even  though  the 
pulse  remains  apparently  unchanged. 

In  Cases  of  Poisoning  with  the  digitalis  series,  the  most  alarming 
symptoms  arise  from  the  circulatory  changes.  In  the  well-known 
case  of  Koppe,  who  accidentally  poisoned  himself  in  the  course  of  his 
investigations  on  digitoxin,  the  first  symptoms  were  uneasiness,  giddi- 
ness, nausea  and  vomiting,  and  great  muscular  weakness.  The  pulse 
then  fell  to  about  half  its  normal  rate  and  became  intermittent,  and 
the  increasing  muscular  weakness  was  accompanied  by  precordial 
anxiety,  imperfect  vision,  and  constant  nausea  and  vomiting,  which 
prevented  sleep  and  rest,  and  which  persisted  for  over  thirty-six  hours 
without  improvement.  The  symptoms  then  slowly  disappeared  and  he 
recovered  entirely  in  about  a  week.  The  quantity  taken  by  him  was 
2  mg.  (^L-  gr.);  but  four  days  previously  he  had  taken  1  mg.  (^  gr.), 


THE  DIGITALIS  SERIES.  451 

and  it  is  possible  that  this  may  not  have  been  absorbed  completely. 
In  any  case  the  small  dose  of  digitoxin  necessary  to  induce  almost 
fatal  symptoms  indicates  that  it  is  one  of  the  most  powerful  poisons 
known  at  present. 

The  main  action  of  this  series  is  on  the  circulation,  but  some  other 
results  of  their  administration  of  less  consequence  have  been  observed. 
Thus  in  fever  the  Temperature  is  not  infrequently  reduced,  although 
it  remains  unchanged  after  the  administration  of  digitalis  to  the  normal 
animal.  This  action  is  said  by  some  to  be  the  result  of  collapse,  while 
others  believe  it  to  be  due  to  the  changes  in  the  circulation,  but 
neither  of  these  seems  to  be  a  very  happy  explanation.  It  has  been 
stated  already  that  the  members  of  this  series  act  as  stimulants  to 
some  parts  of  the  central  nervous  system,  and  a  possible  explanation 
of  their  antipyretic  action  would  be  an  increased  activity  of  the  temper- 
ature-controlling centre.  It  has  been  shown  by  Harnack  that  several 
central  nervous  stimulants,  including  picrotoxin,  cause  a  fall  in  the 
temperature  in  this  way. 

Another  observation  which  has  been  made  in  regard  to  this  series  is  that 
it  tends  to  weaken  and  eventually  to  paralyze  the  Muscles,  and  still  more, 
the  terminations  of  the  peripheral  Nerves  of  the  frog.  For  this  purpose  it 
has  to  be  applied  in  quantities  which  would  at  once  stop  the  mammalian 
heart,  and  this  action  certainly  never  even  commences  in  warm-blooded  an- 
imals. Large  quantities  of  digitalis  are  said  to  act  on  the  unstriated  muscle 
of  several  organs,  such  as  the  stomach  and  uterus,  and  to  increase  their 
movements. 

PREPARATIONS. 

Digitalis  (U.  S.  P.),  Digitalis  Folia  (B.  P.),  foxglove,  the  leaves  of  Digitalis 
purpurea  collected  from  plants  of  the  second  year's  growth.  0.03-0.1  G. 
(i-2grs.). 

Extractum  Digitalis  (U.  S.  P.),  10-20  mgs.  (£-i  gr.). 

Fluidextractum  Digitalis  (U.  S.  P.),  0.05-0.1  c.c.  (1-2  mins.). 

INFUSUM  DIGITALIS,  IT.  S.  P.",  4-8  c.c.  (1-2  fl.  dr.);  B.  P.,  2-4  fl.  drs. 

TINCTURA  DIGITALIS  (U.  S.  P.,  B.  P.),  0.3-1  c.c.  (5-15  mins.). 

"  Digitaline  "  of  commerce  varies  much  in  composition  and  in  dose,  some- 
times proving  entirely  inert,  while  at  other  times  it  has  proved  poisonous  in 
comparatively  small  quantities.  Crystalline  digitaline  very  often  consists 
largely  of  digitonin,  which  is  entirely  devoid  of  the  digitalin  action.  Other 
preparations  seem  to  contain  much  digitophyllin.  "  Digitalinum  verum"  is 
said  to  be  pure  digitalin,  and  may  be  injected  subcutaneously  without  dan- 
ger. 2-6  mg.  GWo  gr.). 

Digitoxin  has  been  prescribed  in  doses  of  TV  mg.  (y^  gr.),  but  the  forms  at 
present  on  the  market  vary  greatly  in  strength. 

The  tincture  and  infusion  are  the  most  commonly  used  preparations. 
The  extract  and  the  powdered  leaves  may  be  given  in  the  form  of  pills.  The 
preparations  ought  to  be  freshly  made,  and  solutions  of  ' '  digitaline  ' '  and  digi- 
toxin must  not  be  kept,  as  they  soon  decompose  and  become  entirely  inert. 

Strophanthus  (U.  S.  P.),  the  seeds  of  Strophanthus  hispidus. 

Strophanthi  Semina  (B.  P.),  the  seeds  of  Strophanthus  Kombe. 

Extractum  Strophanthi  (B.  P.),  \-\  gr. 

TINCTURA  STROPHANTHI  (U.  S.  P.,  B.  P.),  0.3-1.0  c.c.  (5-15  mins.). 
Strophanthinum  (U.  S.  P.),  varies  in  composition  and  in  power.  Its  dose  is  gen- 
erally given  as  1  mg.  (^  gr.),  but  this  is  often  devoid  of  action,  while  in  other 
cases  0. 2  mg.  has  been  found  a  sufficient  dose,  and  it  is  therefore  to  be  used  with 


452  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

caution.  Its  solutions  are  very  liable  to  decompose  and  have  to  be  freshly  pre- 
pared. 

Scilla  (U.  S.  P.,  B.  P.),  squills,  the  bulb  of  Urginea  maritima,  Urginea 
Scilla,  or  Scilla  maritima,  deprived  of  its  dry  membranaceous  outer  scales  and 
cut  into  thin  slices.  0.05-0.2  G.  (1-3  grs.)  in  pills. 

Acetum  Scillce  (U.  S.  P.,  B.  P.),  1-2  c.c.  (15-30  mins.). 

Fluidextractum   Scillce  (U.  S.  P.),  0.05-0.1  c.c.  (1-2  mins.). 

TINCTURA  SCILLA  (U.  S.  P.,  B.  P.),  0.3-1  c.c.  (5-15  mins.). 

SYRUPUS  SCILLA  (U.  S.  P.,  B.  P.),  2-4  c.c.  (30-60  mins.). 

SYRUPUS  SCILLCE  COMPOSITUS  (U.  S.  P.),  containing  senega  and  tartar 
emetic,  0.5-2  c.c.  (10-30  mins.). 

Oxymel  Scillse  (B.  P.),  $-1  fl.  dr. 

Pilula  Scillse  Composita  (B.  P.),  contains  ginger  and  ammoniacum,  4-8  grs. 

PILTJLA  IPECACUANHA  CUM  SCILLA  (B.  P.),  contains  5  per  cent,  opium. 
4-8  grs. 

Squills  is  often  prescribed  in  pill  form  as  a  diuretic  ;  as  an  expectorant 
the  syrup  is  more  often  used.  The  compound  syrup,  U.  S.  P.,  or  the  pill  of 
Ipecac  and  Squill,  B.  P.,  may  be  ordered  instead  of  a  cough  mixture,  as 
they  contain  the  chief  constituents  of  such  remedies. 

Scillitoxin,  etc.,  of  commerce  are  merely  purified  extracts  and  not  pure 
principles. 

Apocynum  (U.  S.  P.),  Canadian  hemp,  the  root  of  Apocynum  cannabi- 
iium. 

Fluidextractum  Apocyni  (U.  S.  P.),  0.3-1  c.c.  (5-15  mins.). 

Convallaria  (U.  S.  P.),  Lily  of  the  Valley,  the  rhizome  and  roots  of  Con- 
vallaria  majalis. 

Fluidextractum  Convallarice  (U.  S.  P.),  0.3-1  c.c.  (5-15  mins.). 

Euonymus  (U.  S.  P.),  Euonymi  Cortex  (B.  P.),  Wahoo,  the  bark  of  the 
roots  of  Euonymus  atropurpureus. 

Extractum  Euonymi  (U.  S.  P.),  0.05-0.2  G.  (1-3  grs.). 
Extractum  Euonymi  Siccum  (B.  P.),  1-2  grs. 

Therapeutic  Uses.  —  The  chief  purpose  for  which  this  series  is  used 
in  therapeutics  is  to  counteract  certain  changes  in  the  circulation,  which 
result  in  the  blood  accumulating  in  the  veins  in  too  large  quantities, 
while  the  arteries  are  less  completely  filled  than  usual.  And  first  of 
all,  in  cases  of  dilatation  of  the  heart  with  a  weak  and  insufficient 
systole,  its  action  is  almost  specific.  This  is  true  whether  one  or  both 
ventricular  chambers  are  affected,  as  long  as  the  cardiac  muscle  itself 
has  not  undergone  degeneration.  In  these  cases  the  action  is  very 
simple  —  the  increased  ventricular  systole  approaches  the  normal,  the 
output  of  the  heart  is  increased,  and  in  some  cases  at  any  rate,  the 
dilatation  is  diminished  by  the  direct  action  of  the  drug.  The  effect 
is  an  increased  velocity  and  pressure  in  the  arteries,  and  an  improved 
nutrition  of  the  whole  body.  The  organ  which  suffers  most  of  all 
under  the  malnutrition  caused  by  dilatation  of  the  chambers  is  the 
heart  itself,  and,  accordingly,  in  these  cases  the  heart  is  found  better 
nourished  and  has  more  tendency  to  hypertrophy  after  digitalis  or  its 
allies.  Eventually  the  walls  of  the  heart  become  so  enlarged  as  to  be 
able  to  carry  on  the  work  without  the  additional  stimulation  of  digitalis, 
and  the  drug  ought  therefore  to  be  stopped.  It  must  be  remembered  that 
the  hypertrophy  of  the  heart  is  not  a  direct  effect  of  this  series,  which 
only  puts  the  organ  in  a  condition  in  which  it  receives  more  nourish- 


THE  DIGITALIS  SERIES.  453 

ment  and  is  therefore  more  likely  to  hypertrophy.  The  effects  in 
these  cases  of  dilatation  seem  to  be  attributable  entirely  to  the  action 
on  the  cardiac  muscle. 

It  is  frequently  stated  that  the  slowing  of  the  heart,  which  allows  the  heart 
more  time  to  rest  and  more  time  to  fill  itself,  is  accountable  for  the  improve- 
ment. But  numerous  other  drugs  slow  the  heart  quite  as  much  and  in  exactly 
the  same  way,  yet  are  of  no  benefit  but  rather  the  reverse  in  those  condi- 
tions in  which  digitalis  is  most  valuable.  Aconitine,  for  example,  slows  the 
heart  by  stimulating  the  vagus  centre,  but  no  one  would  dream  of  using 
aconite  as  a  substitute  for  digitalis  in  dilatation  of  the  ventricles. 

Another  explanation  of  the  action  of  digitalis  in  cardiac  dilatation  is  that 
the  vagus  being  the  trophic  nerve  of  the  heart,  its  stimulation  increases  the 
tendency  of  the  heart  to  hypertrophy,  and  this  series  therefore  causes  hyper- 
trophy by  stimulation  of  the  trophic  nerve.  Any  explanation  which  requires 
the  assumption  of  trophic  nerves  is  fraught  with  danger,  however,  and  this 
one  is  easily  refuted  by  the  fact  that  aconite  does  not  induce  hypertrophy  of 
the  heart. 

The  true  explanation  of  the  action  of  digitalis  is  the  action  on  the  cardiac 
muscle,  by  which  the  systole  is  strengthened  and  the  output  of  the  heart  is 
increased. 

Mitral  incompetency  may  be  taken  as  a  concrete  example  of  cardiac 
disease.  Here  some  of  the  blood,  instead  of  passing  into  the  aorta 
during  the  ventricular  systole,  passes  back  into  the  auricle.  In  course  of 
time  the  auricle  dilates  owing  to  the  pressure  during  its  diastole,  and  the 
consequence  is  that  the  lungs  become  congested,  the  right  ventricle  and 
eventually  the  right  auricle  dilate,  and  the  whole  systemic  circulation 
is  retarded.  (Edema  and  dropsy  follow,  the  kidneys  and  other  organs 
become  overfilled  with  blood,  and  the  whole  economy  is  thrown  into 
disorder.  The  left  ventricle  is  not  affected  directly  by  the  pressure, 
but  it  suffers  in  the  general  malnutrition,  and  may  become  weak  and 
dilated  like  the  rest  of  the  heart.  If  now  one  of  this  series  be  given, 
the  right  and  left  ventricles  commence  to  beat  more  strongly,  their  out- 
put is  increased,  and  the  blood  is  forced  through  the  lungs.  It  still 
regurgitates  into  the  left  auricle,  but  the  proportion  passing  back  to 
that  driven  forward  is  smaller,  owing  to  the  increase  in  systole,  which 
lessens  the  mitral  orifice.  Moreover  the  right  ventricle  is  able  to  over- 
come the  pressure  in  the  pulmonary  artery,  and  therefore  soon  ceases  to 
drive  blood  into  the  right  auricle,  and  the  systemic  veins  can  pass  their 
blood  into  the  heart  without  difficulty.  The  congestion  of  the  organs 
rapidly  disappears,  the  kidneys  become  better  nourished,  and  finding 
large  quantities  of  fluid  accumulated  in  the  body,  at  once  proceed  to 
excrete  it.  The  heart  itself  improves  in  condition,  but  more  work  is 
required  of  it  than  in  the  normal  body,  because  some  of  its  work  is 
still  lost  through  the  blood  passing  backwards  from  the  ventricle  in- 
stead of  forwards.  The  muscle  responds  to  the  strain  by  hypertrophy, 
and  when  this  process  is  complete,  the  drugs  have  fulfilled  their  pur- 
pose, and  further  administration  is  useless  and  may  be  dangerous. 

The  only  action  of  the  drug  required  here  is  the  increased  contraction 
of  the  ventricles  and  auricles  in  systole,  and  this  is  exactly  the  point 


454  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

in  which  this  series  differs  from  all  others.  At  the  same  time,  if  the 
diastolic  dilatation  becomes  less  marked,  as  it  does  in  many  experi- 
ments on  the  normal  heart,  this  must  also  aid  in  such  a  case,  because 
the  more  dilated  the  ventricle,  the  less  perfectly  does  the  mitral  valve 
close  the  auriculo-ventricular  orifice  at  the  beginning  of  systole.  If 
then  the  dilatation  of  the  heart  becomes  less,  either  from  a  direct  action 
of  the  drug,  or  as  a  result  of  the  improved  nutrition  of  the  muscle,  the 
imperfection  of  the  valve  may  be  compensated  for  by  the  narrowing  of 
the  orifice.  If  the  muscular  action  predominates  sufficiently  over  the 
inhibitory,  a  further  factor  may  aid  in  repairing  the  breach  of  the  valve, 
for  the  auricular  muscle  is  acted  on  in  the  same  way  as  the  ventricu- 
lar—  its  contraction  is  more  complete,  and  the  auricle  therefore  emp- 
ties itself  more  perfectly,  and  contains  less  blood  at  the  beginning  of 
the  ventricular  systole  than  it  otherwise  would.  If,  in  addition,  the 
auricular  relaxation  is  lessened  by  digitalis,  a  greater  resistance  must 
be  offered  to  the  regurgitating  blood.  The  increased  contraction  of  the 
papillary  muscles  may  also  aid  in  the  therapeutic  effect  by  closing  the 
valves  more  completely. 

In  aortic  incompetency  the  same  beneficial  results  may  be  expected, 
because  here  again  there  is  more  blood  expelled  into  the  aorta,  and  at 
a  higher  pressure.  The  less  dilated  ventricle  also  presents  a  greater 
resistance  to  the  return  of  the  blood.  It  is  true  that  longer  time  is 
allowed  for  the  blood  to  pass  back  into  the  ventricle  owing  to  the  pro- 
longation of  the  diastolic  pause,  but  this  does  not  seem  to  be  sufficient 
to  counterbalance  the  benefits  of  the  more  complete  contraction  of  the 
ventricle. 

In  narrowing  of  the  orifices,  the  improvement  observed  after  digi- 
talis may  also  be  explained  by  the  stronger  and  more  complete  con- 
traction of  the  ventricles.  Stenosis  very  rarely  occurs  unaccompanied 
by  regurgitation,  however,  and  the  diminution  of  the  backward  flow 
may  be  the  main  object  attained  by  these  drugs  in  this  condition. 

On  the  right  side  of  the  heart  the  same  action  occurs  as  on  the  left, 
and  in  dilatation  of  the  right  ventricle,  which  often  occurs  as  the  result 
of  pulmonary  disease,  this  series  acts  by  increasing  the  strength  of  the 
ventricular  contraction. 

In  numerous  acute  febrile  conditions  the  heart  becomes  affected, 
possibly  in  part  by  the  high  temperature,  but  largely  from  the  toxic 
products  circulating  in  the  blood.  The  chief  cardiac  symptoms  are 
dilatation  with  a  weak  systole  and  a  small  "fluttering"  pulse.  In 
these  cases  digitalis  and  other  similar  drugs  may  be  of  great  service  in 
slowing  the  accelerated  heart  and  in  increasing  the  extent  of  systole, 
and  thus  improving  the  general  circulation.  In  pneumonia  more 
especially,  great  improvement  is  often  seen  after  digitalis.  In  this 
disease,  besides  the  toxic  action  on  the  heart  there  may  be  present 
more  or  less  obstruction  of  the  pulmonary  vessels  through  pressure, 
resulting  in  overwork  and  dilatation  of  the  right  heart.  The  routine 
treatment  of  pneumonia  with  digitalis  is  often  recommended,  but  is  to 
be  deprecated  on  the  general  principle  that  a  drug  is  not  to  be  pre- 


THE  DIGITALIS  SERIES.  455 

scribed  until  some  special  indication  for  it  appears ;  unless  distinct 
evidence  of  circulatory  disturbance  is  present,  digitalis  ought  to  be 
withheld. 

In  acute  fevers  the  inhibitory  mechanism  is  often  less  irritable  than 
normally,  and  the  activity  of  the  drug  must  not  be  estimated  by  the 
slowness  of  the  pulse.  (See  page  450.) 

In  some  forms  of  dilatation  of  the  heart  digitalis  and  its  allies  are 
to  be  avoided.  Thus  where  extensive  degeneration  of  the  heart  mus- 
cle is  present,  as  in  fatty  heart,  little  or  no  benefit  from  the  muscular 
action  is  to  be  expected,  for  the  muscle  itself  is  too  weak  to  respond  to 
the  stimulation.  On  the  other  hand,  digitalis,  by  increasing  the  pressure 
against  which  the  heart  has  to  contract,  may  cause  the  most  serious  re- 
sults— the  systole  becomes  even  weaker  than  before  its  administration, 
and  brain  anaemia,  syncope,  and  not  infrequently  sudden  death  follow. 
In  other  cases,  while  the  condition  of  the  heart  is  eminently  suitable  for 
digitalis  treatment,  disease  of  other  parts  of  the  body  may  preclude  its 
use.  Thus  if  extensive  degeneration  of  the  arterial  coats  is  present,  the 
increased  pressure  in  the  interior  of  the  vessels  may  lead  to  rupture  of 
their  walls  and  apoplexy.  In  those  cases,  if  any  of  the  series  is  to  be 
given,  it  ought  to  be  strophanthus,  which  causes  a  less  extensive  rise 
in  the  blood-pressure  than  digitalis,  and  it  is  recommended  that  either 
be  prescribed  along  with  some  drug  to  dilate  the  vessels  and  lessen 
the  arterial  tension,  such  as  nitroglycerin  or  some  other  of  the  nitrite 
series.  In  treating  with  digitalis  and  a  member  of  the  nitrite  series,  it 
is  found  that  the  digitalis  action  sets  in  somewhat  slowly,  and  persists 
for  a  long  time,  while  the  nitrites  act  rapidly,  but  are  excreted  com- 
paratively soon.  The  best  results  are  therefore  obtained  by  frequent 
small  doses  of  nitroglycerin,  which  need  not  be  administered  for  some 
hours  after  the  first  dose  of  digitalis. 

In  some  cases  dilatation  of  the  heart  seems  to  be  due,  at  any  rate  in 
part,  to  increased  arterial  tension  from  disease  of  the  arterial  walls  and 
of  the  kidneys.  In  these  cases  digitalis  is  to  be  used  with  caution, 
because  of  its  vaso-constrictor  action,  and  perhaps  strophanthus  is  to 
be  preferred  to  digitalis,  unless  one  of  the  nitrite  series  is  associated 
with  the  latter. 

Valvular  disease  is  not  in  itself  an  indication  for  digitalis,  for  the 
heart  tends  to  undergo  compensatory  hypertrophy  in  favorable  condi- 
tions without  the  use  of  any  drug  whatever,  and  digitalis  is  indicated 
only  when  no  such  compensation  occurs.  At  the  same  time  hyper- 
trophy of  the  heart  is  not  a  centra-indication,  as  is  often  stated,  for  a 
special  strain  may  cause  excessive  dilatation  in  a  hypertrophied  heart, 
and  digitalis  may  be  necessary  until  a  second  hypertrophy  has  occurred 
and  restored  the  equilibrium  once  more. 

Digitalis  is  often  prescribed  in  tachycardia  (rapid  heart)  in  order  to 
slow  the  rhythm  only,  but  if  no  other  symptoms  than  acceleration  are 
present,  other  drugs,  such  as  aconite  or  strychnine,  may  be  substituted 
for  digitalis,  and  do  not  entail  the  other  changes  in  the  circulation. 

It  has  been  mentioned  that  the  exhibition  of  digitalis  in  fever  is 


456  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

often  followed  by  a  fall  of  temperature,  and  Traube  recommended  it 
as  an  antipyretic,  but  it  is  no  longer  used  for  this  purpose,  as  the 
modern  antipyretics  are  much  more  powerful  and  certain  in  their 
action,  and  at  the  same  time  are  less  dangerous. 

The  diuretic  action  of  digitalis  is  also  not  advised  except  where 
other  indications  than  a  diminution  of  the  renal  secretion  are  present, 
for  in  ordinary  cases  it  has  much  less  effect  than  caffeine  and  other 
diuretics.  If  the  anuria  be  secondary  to  disturbances  of  the  circula- 
tion, however,  digitalis  is  the  diuretic  par  excellence  and  cannot  be 
replaced  by  any  of  the  ordinary  means  of  promoting  the  urinary  secre- 
tion, although  they  may  advantageously  be  combined  with  it.  Squills 
is  more  frequently  used  as  a  diuretic  than  digitalis,  and  it  seems  prob- 
able that  in  addition  to  its  action  on  the  heart  and  circulation,  it  exer- 
cises some  direct  stimulant  influence  on  the  renal  epithelium.  Squills 
and  digitalis  are  often  prescribed  together,  where  large  accumulations 
of  fluid  have  to  be  removed.  A  famous  pill  used  in  these  cases  con- 
tains a  grain  each  of  digitalis,  squills  and  calomel. 

Several  of  these  drugs  are  of  considerable  benefit  in  pulmonary 
diseases  accompanied  by  cough.  Thus  in  bronchitis,  more  especially 
in  cases  of  old  standing,  the  addition  of  squills  to  an  "  expectorant 
mixture"  is  often  followed  by  the  most  satisfactory  results.  The 
action  here  is  probably  two-fold.  In  the  first  place,  the  right  heart 
may  be  dilated  owing  to  the  frequent  strain  put  on  it  by  coughing, 
and  squills  remedies  this  condition  by  its  usual  cardiac  action.  In  the 
second  place,  all  these  drugs  possess  to  a  certain  extent  emetic  prop- 
erties, and  thus  cause  an  increase  in  the  bronchial  secretion,  and  ren- 
der the  sputum  less  tenacious  and  more  easily  expectorated.  The 
addition  of  squills,  in  which  this  property  is  more  developed  than  in 
the  others,  has  the  same  effect  as  the  prescription  of  ipecacuanha, 
along  with  the  further  action  on  the  heart. 

Digitalis  is  sometimes  prescribed  to  stop  haemorrhages,  but  though 
it  constricts  the  vessels  it  accelerates  the  flow  through  them,  and,  as  in 
the  case  of  other  haemostatics,  the  benefits  arising  from  the  treatment 
are  problematical.  In  the  circulatory  weakness  following  severe  hem- 
orrhage and  shock  the  effects  of  this  series  would  seem  to  be  indi- 
cated, were  it  possible  to  elicit  their  action  sufficiently  rapidly.  Unfor- 
tunately many  hours  generally  elapse  before  the  heart  and  vessels  are 
affected,  when  they  are  exhibited  by  the  mouth.  These  conditions  are 
generally  treated  by  more  rapidly  acting  measures,  such  as  the  intra- 
venous injection  of  salt  solution  ;  the  effects  of  this  treatment  are 
maintained  much  longer  if  a  small  quantity  of  digitalis  tincture  is 
added  to  the  salt  solution. 

Squills  was  at  one  time  used  as  an  emetic,  but  this  cannot  be  recom- 
mended, owing  to  the  danger  of  its  absorption.  Euonymus  has  been 
employed  as  a  purgative  more  frequently  than  as  a  cardiac  remedy. 
(See  page  107.) 

Some  conditions  in  which  the  cardiac  action  of  this  series  is  to  be 
elicited  only  with  the  greatest  caution,  have  been  already  indicated. 


THE  DIGITALIS  SERIES.  457 

A  further  danger,  which  attends  the  use  of  digitalis  perhaps  more 
than  that  of  the  rest  of  the  series,  is  due  to  its  Cumulative  Action. 
For  the  first  day  or  two  after  the  exhibition  of  this  drug  no  effects 
may  be  noted  in  the  pulse  or  general  circulation  ;  the  ordinary  symp- 
toms are  then  produced,  and  if  the  drug  be  continued,  remain  fairly 
constant  for  some  time.  Sometimes  much  more  marked  symptoms  of 
digitalis  action  appear  suddenly,  however,  —  the  pulse  becomes  alarm- 
ingly slow  and  irregular,  the  patient  complains  of  weakness  and  faint- 
ness,  nausea  and  occasionally  vomiting,  in  fact  the  symptoms  of  the 
second  stage  set  in.  This  is  known  as  cumulative  action,  and  is  prob- 
ably due  to  irregularities  in  the  absorption  and  excretion  or  destruction 
of  the  poison.  It  is  known  that  the  absorption  is  slow,  for  12—36 
hours  may  elapse  before  any  effects  follow  the  exhibition  of  the  drug. 
On  the  other  hand,  the  excretion  or  destruction  must  be  equally  slow, 
for  the  symptoms  sometimes  last  for  several  days  after  it  has  been  dis- 
continued. If  then  anything  happens  to  disturb  the  equilibrium  of 
absorption  and  excretion,  if,  for  example,  the  excretion  is  slower  than 
usual,  or  if  any  irritation  of  the  stomach  and  intestines  causes  a  more 
rapid  absorption,  the  drug  accumulates  in  the  blood,  and  the  same 
effect  is  produced  as  if  a  poisonous  dose  had  been  administered.  In 
order  to  avoid  this  cumulative  effect,  the  condition  of  the  pulse  must 
be  carefully  controlled,  and  as  soon  as  the  circulation  shows  any  signs 
of  excessive  action,  the  drug  ought  to  be  discontinued  for  one  or  two 
days  and  resumed  in  smaller  quantities.  These  cases  of  poisoning  are 
not  serious  if  observed  in  time.  All  of  the  digitalis  series  hitherto 
examined  prove  to  be  cumulative  in  their  action,  but  some  of  them, 
notably  digitoxin,  are  much  more  dangerous  than  others.  In  fact, 
according  to  Fraenkel,  digitoxin  can  only  be  used  safely  in  doses  which 
induce  no  changes  in  the  pulse  for  several  days,  for  if  the  pulse  be 
slowed  by  a  single  dose,  its  repetition  within  twenty-four  hours  induces 
severe  poisoning. 

Another  disagreeable  feature  observed  in  the  use  of  this  series  is  the 
action  on  the  stomach  and  intestine.  As  has  been  noted  already,  the 
local  action  may  produce  the  usual  symptoms  of  gastric  irritability, 
and  the  patient  suffers  from  loss  of  appetite,  nausea  and  gastric  dis- 
comfort, just  when  it  is  important  that  the  nutrition  should  be  the  best 
attainable.  Numerous  attempts  have  therefore  been  made  to  obtain 
preparations  which  possess  the  cardiac  without  the  local  action.  Some 
of  these  seem  to  be  fairly  free  from  irritant  properties ;  for  example, 
some  of  the  digitalines  can  even  be  injected  subcutaneously  without 
giving  rise  to  any  irritation  or  inflammation.  But  unfortunately  all 
those  preparations  vary  so  much  in  strength,  even  when  prepared  by 
the  same  method,  that  their  use  is  scarcely  to  be  recommended.  At 
the  same  time,  in  cases  where  the  ordinary  pharmacopoeial  preparations 
cause  marked  gastric  irritation,  some  of  the  so-called  "  pure  principles  " 
may  be  made  use  of  with  advantage. 

So  little  is  known  regarding  the  comparative  action  of  the  members 
of  this  series  that  the  special  indications  for  each  individual  are  alto- 


458  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION 

gether  indefinite.  It  is  recognized  that  strophanthus  acts  less  on  the 
vessels  than  digitalis,  and  this  gives  an  indication  for  its  use  in  some 
cases.  On  the  other  hand,  squills  acts  more  on  the  kidneys  than  either, 
and  is  therefore  given  frequently  as  an  adjuvant  to  digitalis  in  cases 
where  diuresis  is  desired.  It  also  irritates  the  gastric  mucous  mem- 
brane more,  and  is  often  used  as  an  expectorant.  But  the  details  of 
the  action  of  each  are  still  to  be  worked  out.  One  important  question, 
which  is  practically  unbroken  ground,  is  the  relative  action  of  each  on 
the  vagus  centre  and  on  the  heart.  The  beneficial  results  from  the  use 
of  digitalis  are,  as  has  been  pointed  out  already,  to  be  ascribed  almost 
entirely  to  its  action  on  the  cardiac  muscle.  The  stimulation  of  the 
vagus  may  conceivably  lessen  the  benefits  of  the  cardiac  action  by 
weakening  the  auricular  contraction  and  slowing  the  rhythm,  so  that 
it  would  be  of  considerable  interest  and  importance  to  find  a  drug 
having  the  same  cardiac  action  without  the  inhibitory,1  and,  failing  in 
this,  to  compare  the  eifects  of  digitalis  alone  with  those  of  digitalis  and 
a  drug  which  weakens  the  inhibitory  action.  This  would  have  to  be 
given  in  quantities  sufficient  to  prevent  an  increased  inhibition  without 
cutting  off  the  normal  restraining  impulses  which  pass  down  the  vagi, 
and  the  treatment  would  be  rendered  considerably  more  difficult. 

BIBLIOGRAPHY. 

The  bibliography  on  the  digitalis  series  is  so  extensive  that  the  student  can  only  be 
referred  to  that  given  by  the  following  authors. 

Boehm.     Pfl tiger's  Arch.  f.  d.  ges.  Physiol.,  v.,  p.  153. 

Schmiedeberg.     Arch.  f.  exp.  Path.  u.  Pharm.,  xvi.,  p.  149. 

Robert.     Ibid.,  xxii.,  p.  77. 

Francois- Franck.     Clinique  medicale  de  la  Charite.     Paris,  1894,  p.  549. 

Cushny.     Journ.  of  Exp.  Med.,  ii.,  p.  233. 

Harnack.     Berl.  klin.  Woch.,  1895,  p.  759.     (Erythrophloeine.) 

Marshall.     Journ.  of  Physiol.,  xxii.,  p.  1. 

Pfaff.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxii.,  p.  1. 

.Klingenberg.     Ibid.,  xxxiii.,  p.  353. 

Goldenberg.     Inaug.  Diss.,  Dorpat,  1892. 

Jarmerstedt.     Arch.  f.  exp.  Path.  u.  Pharm.,  xi.,  p.  22.     (Scilla.) 

Cervello.     Ibid.,  xv.,  p.  235.      (Adonis.) 

Fraser.     Trans.  Koy.  Soc.  Edinburgh,  1890  and  1891.      (Strophanthus. ) 

Fraser  and  Tillie.     Arch,  internat.  de  Pharmacodyn.,  v.,  p.  349.      (Acokanthera. ) 

Prevost.     Trav.  du  Lab.  therapeut.  exp.,  ii.,  p.  221. 

Lewin.     Virchow's  Arch.,  cxxxiv.,  p.  231  ;  cxxxvi.,  p.  83;  cxxxviii.,  p.  283. 

Kiliani.     Arch,  der  Pharmacie,  1892-1899. 

Hedbom.     Skandin.  Arch.  f.  Phys.,  viii.,  p.  185.    Arch.  f.  exp.  Path.,  xlv.,  p.  317. 

Fraenkel.     Arch.  f.  exp.  Path.  u.  Pharm.,  xl,  p.  40 ;  Ii.,  p.  84. 

Resh.     Ibid.,  xliii.,  p.  130. 
.     Straub.     Ibid.,  xlv.,  p.  317. 

Cloetta.     Ibid.,  xlv.,  p.  435. 

Gottlieb,  Sahli,  etc.     Verhandl.  d.  Congress  f.  inn.  Med.,  1901. 

Wybauw.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv.,  p.  434. 

Braun  u.  Mager.    Sitzungsb.  d.  Wiener  Akad.  Math,  naturwissen.  Cl.,  cviii.,  iii.,  p.  471. 

Faust.  Ueber  Bufonin  u.  Bufotalin,  Leipsig,  1902 ;  Arch.  f.  exp.  Path.  u.  Pharm., 
xlix.,  p.  1. 

Gottlieb  and  Magnus.  Arch.  f.  exp.  Path.  u.  Pharm.,  xlvii.,  p.  135;  xlviii.,  p.  262; 
Ii.,  p.  30. 

Faust.     Ibid.,  xlviii.,  p.  272.     (Acocantherin.) 

Loeb.     Ibid.,  Ii.,  p.  64. 

1  Helleborein  has  comparatively  little  action  on  the  inhibition,  but  in  a  number  of 
cases  of  cardiac  disease  in  which  I  have  attempted  to  substitute  it  for  digitalis  it  induced 
irritation  of  the  intestine  and  diarrhoea  through  its  local  irritant  action. 


SUPRARENAL   OR  ADRENAL   GLANDS.  459 


XXIX.  SUPRARENAL  OR  ADRENAL  GLANDS. 

The  suprarenal  capsules  of  animals  have  recently  been  shown  to 
contain  a  body  which  possesses  a  powerful  action  on  the  organism,  and 
which  the  glands  normally  secrete  into  the  blood  vessels.  The  active 
principle,  which  seems  to  be  rather  unstable,  has  been  isolated  in  two 
forms — Epinephrine  (Abel)  and  Adrenaline  (Takamine  and  Aldrich) 
or  Suprarenine  (Fiirth).  Some  chemical  differences  exist  between 
epinephrine  and  adrenaline,  but  they  are  very  nearly  related,  and  the 
one  appears  to  be  readily  changed  to  the  other  by  simple  chemical 
manipulations ;  each  elicits  the  characteristic  effects  in  living  tissues, 
and  each  molecule  appears  to  contain  a  dioxybenzol  radicle. 

FIG.  46. 


Tracing  of  the  blood-pressure  under  the  influence  of  extract  of  suprarenal  gland,  which  was  in- 
jected into  the  jugular  vein  at  a. 

In  the  frog,  the  suprarenal  extract  causes  paralysis  of  the  central 
nervous  system,  which  is  of  only  short  duration,  however,  even  when 
large  quantities  are  injected.  In  mammals  the  hypodermic  application 
of  large  doses  is  followed,  as  a  general  rule,  by  some  excitement,  agita- 
tion, and  often  tremors,  although  these  are  not  marked  in  the  rabbit ; 
vomiting  has  frequently  been  observed  in  dogs.  This  stage  is  fol- 
lowed by  paresis  of  the  hind  limbs,  often  by  rapid  respiration  and 
dyspnoea,  and  eventually  by  failure  of  the  respiration  and  death.  In 
some  animals  the  urine  is  increased  in  quantity,  and  haemorrhages 
occur  from  the  mucous  membranes  and  from  the  kidney.  It  is  to  be 
noted  that  only  large  quantities  of  the  gland  are  fatal  when  they  are 
injected  hypodermically,  and  it  may  be  doubted  whether  any  symptoms 
can  be  produced  when  it  is  absorbed  from  the  stomach  and  intestines. 

On  the  other  hand,  comparatively  small  quantities  elicit  marked 
symptoms  when  they  are  injected  into  the  blood  vessels,  these  consist- 
ing in  a  very  rapid  and  very  pronounced  rise  of  the  blood-pressure, 
with  slowing  and  strengthening  of  the  heart  beat.  The  action  of  the 


460  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

suprarenal  extract  injected  into  a  vein  is  in  short  that  of  the  members 
of  the  digitalis  series.  The  slowness  of  the  pulse  is  due  to  stimulation 
of  the  pneumogastric  centre  in  the  medulla  oblongata,  while  the  heart 
muscle  is  affected  in  the  same  way  as  by  digitalis,  that  is,  its  systole  is 
much  strengthened  and  its  diastole  is  often  rendered  less  complete. 
The  rise  in  the  blood-pressure  is  due  chiefly  to  a  marked  contraction 
of  the  peripheral  arterioles  from  direct  action  on  the  muscular  coats, 
in  part  to  the  increased  efficiency  of  the  cardiac  contractions,  perhaps 
in  part  to  stimulation  of  the  vaso-motor  centre. 

The  extract  differs  from  the  digitalis  series  chiefly  in  the  rapidity 
with  which  these  changes  are  elicited,  in  the  rise  of  blood-pressure 
being  greater,  and  in  the  action  passing  off  more  quickly.  Mere  traces 
of  epinephrine  are  sufficient  to  cause  this  change  in  the  blood-pressure 
when  they  are  injected  intravenously,  while  no  distinct  effect  is  pro- 
duced by  much  larger  quantities  injected  subcutaneously  or  adminis- 
tered by  the  mouth. 

Large  quantities  of  the  extract  injected  into  a  vein  cause  the  same 
form  of  irregularity  as  the  members  of  the  digitalis  series,  and  in  one 
case  fibrillary  contraction  of  the  heart  has  been  observed  from  it. 
The  frog's  heart  seems  to  be  acted  on  less  by  suprarenal  extract 
than  the  mammals',  but  Oliver  and  Schafer  observed  changes  in  it- 
similar  to  those  induced  by  digitalis. 

Some  of  the  vessels  do  not  seem  to  be  influenced  by  it  so  much  as 
others ;  thus  the  pulmonary  vessels  are  not  narrowed  at  all  or  only 
very  slightly,  and  even  the  direct  application  of  the  extract  to  the 
lungs  does  not  cause  pallor.  The  cerebral  vessels  also  seem  to  undergo 
no  constriction  and  in  fact  some  evidence  of  their  dilatation  is  pre- 
sented by  the  widening  of  the  retinal  vessels.  This  is  due  to  the  con- 
striction of  the  vessels  in  other  parts  of  the  body  which  diverts  to  the 
brain  a  larger  amount  of  blood  than  usual.  Gerhardt  states  that  the 
vessels  of  muscle  are  scarcely  changed  in  calibre,  while  those  of  the 
skin  are  contracted,  but  not  in  so  marked  degree  as  those  of  the  abdom- 
inal organs.  The  constriction  of  the  vessels  of  the  stomach,  intestine 
and  other  organs  whose  blood  flow  is  regulated  by  the  splanchnic 
nerve,  is  apparently  the  chief  factor  in  the  rise  of  blood-pressure, 
although  the  action  is  by  no  means  confined  to  these.  Even  neighbor- 
ing organs  vary  considerably  in  their  reactions ;  for  example,  the 
uterine  vessels  are  constricted  while  those  of  the  bladder  are  much  less 
affected. 

The  contraction  of  the  vessel  walls  may  be  demonstrated  by  perfus- 
ing blood  containing  epinephrine  or  the  gland  extract  through  the  artery 
of  an  excised  organ,  for  very  much  less  blood  escapes  from  the  vein 
than  when  pure  blood  is  used.  Or  a  solution  of  the  extract  may  be 
applied  to  the  exposed  mesentery,  when  the  vessels  are  often  entirely 
obliterated.  The  mucous  membranes  are  similarly  affected  as  is  well 
seen  in  irritation  of  the  conjunctiva,  for  the  redness  and  congestion 
give  place  to  pallor  when  epinephrine  solution  is  applied.  It  has  no 


SUPRARENAL  OR  ADRENAL  GLANDS.  461 

effect  on  the  unbroken  skin,  through  which  it  is  unable  to  penetrate  to 
the  vessels,  but  denuded  surfaces  become  pale  and  anaemic  under  its 
influence  and  haemorrhages  cease  from  the  smaller  vessels  and  capil- 
laries. 

In  addition  to  the  vessels  a  number  of  other  forms  of  unstriated 
muscle  are  thrown  into  a  condition  of  spasmodic  contraction  by  supra- 
renal extract.  Thus  the  muscular  fibres  of  the  eye  that  are  innervated 
from  the  superior  cervical  ganglion  undergo  contraction  when  the  drug 
is  injected  intravenously  or  applied  locally.  This  results  in  dilatation 
of  the  pupil,  withdrawal  of  the  nictitating  membrane,  separation  of  the 
eyelids  and  protrusion  of  the  eyeball,  exactly  as  after  cocaine  or  stimu- 
lation of  the  cervical  sympathetic.  The  muscle  fibres  supplied  by  the 
third  nerve  are  unaffected.  The  contraction  of  some  involuntary 
muscles  is  inhibited  by  suprarenal  extract,  so  that  the  cardiac  sphincter 
of  the  stomach  and  the  internal  anal  sphincter  relax,  and  the  move- 
ments of  the  stomach,  intestine  and  bladder  are  retarded  or  altogether 
arrested.  The  uterus,  vagina,  vas  deferens,  seminal  vesicles,  and  the 
external  genital  organs  are  all  contracted  and  anaemic  in  contrast  to 
the  relaxed  condition  of  the  stomach  and  intestine. 

Adrenalin  thus  acts  on  a  large  number  of  forms  of  involuntary 
muscle  and  apparently  in  diametrically  opposite  ways,  causing  con- 
striction in  many  cases,  but  inhibiting  it  in  others.  It  is  noted  that 
stimulation  of  the  sympathetic  nerves  has  similar  results  in  most  cases ; 
for  example,  stimulation  of  the  splanchnic  nerves  contracts  the  intes- 
tinal vessels,  but  relaxes  the  muscular  coats  of  the  bowel.  Many 
observers  have  therefore  ascribed  the  effects  of  suprarenal  extract  to 
its  stimulating  the  terminations  of  the  nerves  and  not  to  its  acting  on 
the  muscle  fibres  directly.  The  objection  is  raised,  however,  that  the 
action  persists  after  degeneration  of  the  nerve-endings,  and  this  seems 
to  indicate  that  the  drug  acts  on  the  muscle  fibres  and  that  the  differ- 
ence in  the  results  depends  on  fundamental  differences  in  the  chemical 
characters  of  these  fibres. 

The  secretions  of  the  salivary  glands  and  of  the  mucous  glands  of 
the  mouth  and  throat  are  increased,  apparently  through  stimulation  of 
the  nerve  terminations,  as  under  pilocarpine.  The  secretion  is  arrested 
by  atropine,  but  can  be  reinstated  by  larger  amounts  of  suprarenal 
extract,  which  is  a  more  powerful  antagonist  to  atropine  than  pilocar- 
pine. The  lachrymal  glands  and  the  bile  are  also  increased,  while 
the  secretion  of  the  pancreatic  juice  and  of  the  sweat  is  probably 
unchanged. 

Suprarenal  gland  extract  injected  hypodermically  or  intraperito- 
neally  causes  glycosuria  from  an  excessive  formation  of  sugar  in  the 
liver ;  this  appears  to  be  due  not  to  direct  action  on  the  liver,  but  to  a 
secondary  effect  from  the  pancreas,  for  adrenaline  applied  directly  to 
the  latter  has  the  same  effect. 

The  action  of  adrenaline  on  the  blood  vessels  is  of  very  short 
duration,  and  this  has  been  ascribed  to  its  being  rapidly  excreted  or 


462  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

oxidized ;  recent  experiments  have  shown  that  neither  of  these  expla- 
nations suffices,  for  if  the  circulation  is  shut  off  from  a  limb  before  the 
injection  of  adrenaline  into  the  general  circulation,  and  the  ligature  is 
removed  only  after  the  effects  on  the  other  tissues  have  passed  off,  the 
vessels  of  the  previously  occluded  limb  contract  vigorously ;  this  indi- 
cates that  enough  of  the  drug  is  still  present  in  the  blood  to  contract 
fresh  unpoisoned  vessels,  although  those  at  first  affected  no  longer 
respond  to  it. 

Preparations. — Extracts  were  at  first  made  from  the  fresh  glands, 
but  soon  the  dried  glands  were  introduced — glandules  suprarenales 
siccce  (U.  S.  P.),  the  dried  glands  of  the  sheep  or  ox — and  a  watery 
solution  made  from  these  may  be  used.  The  active  principle  has  been 
put  on  the  market  under  the  name  of  ADRENALINE,  and  this  has  almost 
entirely  supplanted  the  cruder  preparations.  It  is  generally  used  in 
1  per  mille  solution,  but  often  in  one-tenth  or  even  one-fiftieth  of 
this  strength.  This  solution  may  be  disinfected  by  boiling,  and  does 
not  induce  any  general  symptoms  unless  when  injected  intravenously 
and  rapidly. 

Therapeutic  Uses. — Disease  of  the  suprarenal  gland  leads  to  a  series 
of  symptoms  known  as  Addison's  disease,  and  it  has  been  supposed 
that  the  extract  of  the  gland  might  counteract  this  condition  by  sup- 
plying the  substance  whose  deficiency  induced  the  symptoms.  As  a 
matter  of  fact,  however,  but  little  success  has  attended  its  use  for  this 
purpose,  and  the  failure  may  perhaps  be  due  to  the  method  of  applica- 
tion, for  it  has  been  shown  repeatedly  that  the  characteristic  effects  of 
epinephrine  cannot  be  elicited  by  its  administration  by  the  mouth  or 
subcutaneously.  It  is  possible  that  the  extract  might  prove  beneficial 
if  it  could  be  brought  into  the  blood  directly  but  this  is  quite  impos- 
sible in  a  chronic  condition  such  as  Addison's  disease.  Its  general  action 
on  the  circulation  might  be  taken  advantage  of  in  such  emergencies  as 
heart  failure  under  anesthesia  or  in  shock,  and  in  fact  Gottlieb  has 
shown  that  in  animals  poisoned  with  chloral  or  chloroform  until  the 
pulse  has  almost  completely  ceased,  the  circulation  may  be  restored 
immediately  by  suprarenal  extract.  In  order  to  elicit  this  action,  the 
drug  would  have  to  be  injected  intravenously  and  little  danger  is  to 
be  apprehended  from  small  doses  if  one  can  judge  from  the  results  in 
animals ;  no  such  treatment  has  yet  been  adopted  in  man. 

The  great  use  of  suprarenal  preparations  is  however  due  to  its  local 
effects  on  the  vessels.  No  other  body  is  known  which  induces  such  com- 
plete contraction  of  the  vessels  in  any  part  to  which  it  is  applied,  and 
in  addition  suprarenal  extract  has  only  local  effects,  unless  injected 
into  the  blood.  Complete  bloodlessness  of  a  part  may  thus  be  elicited 
without  alteration  of  the  general  blood-pressure,  and  in  fact  without 
any  appreciable  effect  upon  other  parts  of  the  body.  This  local 
ischsemia  has  been  largely  employed  to  allow  of  bloodless  operations 
on  the  eye  and  to  remove  congestion  of  the  conjunctiva  from  various 
causes.  It  is  often  administered  with  cocaine  in  operations  on  the  eye 


SUPRARENAL   OR  ADRENAL   GLANDS.  463 

(1  in  10,000  solution  of  adrenaline).  In  congestion  of  the  nasal 
mucous  membrane  and  in  operations  on  the  nose  it  is  also  used  exten- 
sively and  with  much  success ;  the  1  per  mille  solution  may  be 
sprayed  into  the  nose,  or  cotton  soaked  in  it  may  be  packed  into  the 
cavity.  In  epistaxis  and  in  operations  on  the  nose,  the  haemorrhage 
ceases  almost  completely  and  the  contraction  of  the  mucous  membrane 
permits  of  a  clearer  view  of  the  field  of  operation.  Hay  fever  is 
often  relieved  by  similar  treatment  with  suprarenal  preparations.  A 
solution  of  adrenaline  has  been  found  useful  in  haemorrhage  from  the 
ear,  mouth  and  throat,  and  in  controlling  haemorrhage  in  operations  in 
general  surgery. 

Griinbaum  first  suggested  its  administration  by  the  mouth  in  gastric 
haemorrhage,  in  which  the  action  is  confined  to  the  mucous  membrane 
of  the  stomach.  Similarly  it  may  be  injected  into  the  rectum,  bladder 
and  uterus  in  congestion  or  haemorrhage  from  these  organs,  and  Schiifer 
recommends  it  especially  in  post-partum  haemorrhage,  in  which  it  acts 
not  only  on  the  uterine  vessels  but  also  on  the  muscular  walls,  and 
arrests  the  bleeding  by  causing  a  tonic  contraction.  In  all  of  these 
cases  the  suprarenal  preparation  has  to  be  applied  directly  to  the 
bleeding  organ ;  and  no  effects  will  follow  from  its  being  carried  to 
them  by  the  circulation.  The  local  contraction  of  the  vessels  lasts 
very  much  longer  than  that  induced  by  intravenous  injection,  for  even 
dilute  solutions  induce  ischaemia  lasting  from  thirty  minutes  to  two 
hours,  according  to  the  rapidity  with  which  the  extract  is  absorbed. 
The  vessels  of  some  organs  do  not  contract  under  adrenaline,  and  no 
benefit  is  to  be  expected  from  its  application  in  haemorrhage  from 
these ;  spraying  adrenaline  into  the  lungs  in  case  of  haemoptysis,  for 
example,  is  quite  useless,  and  similarly  haemorrhage  in  operations  on 
the  brain  cannot  be  controlled  by  it. 

The  constriction  of  the  vessels  in  a  part  to  which  adrenaline  is 
applied  retards  the  absorption  of  poisons  injected  with  the  adrenaline, 
and  at  the  same  time  permits  of  their  exercising  a  more  marked  local 
effect.  This  fact  has  been  utilized  in  surgery  to  prevent  the  absorp- 
tion of  cocaine  and  intensify  its  local  action,  and  the  method  has  been 
attended  with  most  encouraging  results.  A  few  drops  of  the  1  per 
mille  solution  are  added  to  the  Schleich's  solution  of  cocaine,  and 
blanching  of  the  tissues  results ;  eucaine  does  not  give  such  a  satisfac- 
tory reaction. 

BIBLIOGRAPHY. 

Oliver  and  Schdfer.  Journ.  of  PhysioL,  xviii.,  p.  230.  Brit.  Med.  Journ.,  1901,  i., 
p.  1009. 

Szymonowkz.     Pfliiger's  Arch.,  Ixiv.,  p.  97. 

Bates.     New  York  Med.  Journ.,  Ixiii.,  p.  647. 

Vincent.     Journ.  of  PhysioL,  xxii.,  pp.  Ill  and  270. 

Bardier.     Arch,  de  Phys.  (5),  x.,  p.  370.     Joum.  de  PhysioL,  -.,  p.  950. 

Gottlieb.     Arch.  f.  exp.  Path.  u.  Pharra.,  xxxviii.,  p.  99. 

Abel.  Ztschr.  f.  phvs.  Chem.,  xxviii.,  p.  318.  Johns  Hopkins  Hospital  Bulletin. 
July,  1897;  Nov.,  1901*;  Feb.,  1902. 


464  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Lewandowsky.     Arch.  f.  [Anat.  u.]  Phys.,  1899,  p.  360. 
Boruttau.     Pfliiger's  Arch.,  Ixxviii.,  p.  97. 
Gerhardt.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv.,  p.  161. 
Langley.     Journ.  of  Physiol.,  xxvii.,  p.  237. 
Griinbaum.     Brit.  Med.  Journ.,  1900,  ii.,  p.  1307. 
Amberg.     Arch,  internat.  de  Pharmacodyn..  xi.,  p.  57. 

Herter  and  Wakeman.     Amer.  Journ.  Med.  Sciences,  cxxv.,  p.  46.    Virchow's  Arch., 
clxix.,  p.  479. 

Weiss  and  Harris.     Pfl tiger's  Arch.,  ciii.,  p.  510. 
Meltzer  and  Auer.     Amer.  Journ.  of  Phys.,  xi. 
Brodie  and  Dixon.     Journ.  of  Physiol.,  xxx.,  p.  491. 
Lowen.     Arch.  f.  exp.  Path.  u.  Pharm.,  li..  p.  415. 
Braun.     Arch.  f.  klin.  Chir.,  Ixix. 


XXX.    THE  NITRITES. 

The  nitrites  would  naturally  fall  among  the  inorganic  salts,  but  they 
act  chiefly  upon  the  circulation,  so  that  it  is  convenient  to  place  them 
near  the  digitalis  series. 

Those  which  have  been  examined  more  carefully  are  the  Nitrite  of 
Sodium,  and  the  Nitrous  Ethers  of  the  methane  series,  especially  the 
Nitrite  of  Amyl,  which  is  largely  used  in  therapeutics.  In  these  com- 
pounds the  radicle  —  NO  is  attached  to  the  metal  or  alkyl  through 
an  atom  of  oxygen,  the  formulae  being  K  —  O — NO,  CH3 — O — NO, 
C3H7  — O— NO,  C5Hn— O— NO,  etc.,  and  the  chief  constituent  is  the 
O  —  NO,  the  metal  or  radicle  being  of  less  importance.  A  closely 
allied  series  of  bodies  are  the  nitrates,  in  which  the  nitrogen  has  five 
affinities  and  is  connected  again  to  the  metal  or  radicle  by  oxygen, 
K— O— N02,  CH3— O  — N02,  C6Hn— O— NO2,  etc.  The  metallic 
nitrates  differ  entirely  from  the  nitrites  in  their  effects  and  will  be  dis- 
cussed along  with  the  other  inorganic  salts.  Some  of  the  Nitric  Ethers, 
however,  undergo  a  reduction  when  brought  into  contact  with  organic 
matter,  and  nitrites  are  thus  formed,  so  that  these  bodies  have  effects 
very  similar  to  those  of  the  true  nitrites,  and  have  to  be  discussed 
along  with  them.  The  best  known  of  such  nitrates  is  the  so-called 
Nitroglycerin,  which  is  really  the  trinitrate  of  glycerin,  (CH2(ONO2)- 
CH(ONO2)CH2(ONO2)),  and  is  broken  up  by  alkalies  into  a  mixture 
of  nitrates  and  nitrites.  The  nitrates  have  practically  no  action  in  the 
small  quantities  given,  so  that  almost  all  the  effects  of  nitroglycerin 
are  due  to  the  nitrite  formed.1  Many  other  organic  nitrates  also  form 
nitrites  in  the  tissues,  but  none  of  them  with  such  rapidity  as  nitro- 
glycerin. 

Two  which  have  been  used  to  some  extent  in  the  last  few  years  are  solids 
— Erythrol  Tetranitrate  and  Mannitol  Hexanitrate.  They  act  much  more 
slowly  and  for  a  longer  time  than  nitroglycerin. 

Another  series  of  bodies  which  may  be  mentioned  as  occasionally  acting 
like  nitrites,  although  more  feebly,  are  the  nitro-bodies.  In  these  the  nitro- 

1  Some  doubt  has  been  expressed  of  late  years  as  to  whether  this  reduction  to  nitrite 
really  occurs  in  the  tissues,  and  some  grounds  exist  for  the  belief  that  nitroglycerin  acts 
as  such  (Marshall). 


THE  NITRITES.  465 

gen  is  attached  to  the  alkyl  directly,  and  not  through  the  intervention  of  an 

H 
oxygen  atom.     Examples  of  these  are  Nitromethane,  HC — NO2,  and  Xitro- 

H  H 

ethane,  CH3 — C — NO,.     Their  action  is  so  feeble  as  to  preclude  their  use  in 

H 

therapeutics,  and  seems  due  to  the  — NO2  being  split  off  in  the  tissues  and 
reduced  to  nitrites  in  very  small  quantity. 

The  best  known  member  of  the  group  is  Amyl  Nitrite,  and  its  action 
will  first  be  described,  while  the  points  in  which  the  effects  of  the 
other  members  diverge  from  it  will  be  discussed  later. 

The  characteristic  results  of  the  absorption  of  amyl  nitrite  are  dila- 
tation of  the  vessels  and  the  formation  of  methsemoglobin. 

Symptoms.  —  After  the  inhalation  of  a  few  drops  of  amyl  nitrite,  the 
face  becomes  flushed,  and  the  patient  complains  of  a  feeling  of  fulness 
and  throbbing  in  the  head.  Some  headache  and  confusion  is  often  pre- 

FIG.   47. 


A  B  c 

Tracing  of  the  blood -pressure  in  the  rabbit  under  amyl  nitrite.  From  A  to  B,  the  blood-pressure  is 
the  normal.  At  B  the  inhalation  was  begun  and  the  disturbance  of  the  respiration  is  reflected  in  the 
blood-pressure  tracing.  Immediately  afterwards  the  blood-pressure  begins  to  fall  and  continues  to  do 
so  even  after  the  inhalation  ceased  at  C.  Note  that  the  rhythm  and  strength  of  the  pulse  are  compar- 
atively little  altered. 

sent,  the  pulse  is  accelerated,  and  the  respiration  is  somewhat  quicker 
and  deeper.  The  flush  is  often  confined  to  the  face  and  neck,  but  some- 
times spreads  over  the  whole  trunk,  and  passes  off  in  a  few  minutes, 
unless  the  inhalation  is  continued.  If  large  quantities  of  the  drug  be 
inhaled  at  once,  however,  or  if  the  inhalation  be  continued  for  some 
time,  a  feeling  of  giddiness,  weakness  and  eventually  stupor  follow, 
the  pulse  becomes  slow,  while  the  respiration  still  remains  accelerated, 
but  is  shallower  and  often  somewhat  irregular ;  convulsive  movements 
may  occur,  but  in  general  large  quantities  may  be  taken  Avithout  actual 
danger  in  the  human  subject.  The  blood  is  said  to  have  assumed  a 
dark  color  in  some  cases,  but  this  seems  to  be  rare. 

Action  :  Circulation.  —  In  experiments  on  animals,  the  flushing  and 
dilatation  of  the  arterioles  of  the  head  is  found  to  be  accompanied  and 
followed  by  a  profound,  fall  in  the  blood-pressure.  The  heart  is  accel- 
erated at  the  same  time,  and  seems  not  to  be  responsible  for  the  change. 
The  cause,  as  has  been  repeatedly  demonstrated,  is  the  dilatation  of 
the  peripheral  vessels,  both  arterioles  and  veins  widening  very  consid- 
erably under  the  influence  of  the  drii£ ;  the  vessels  of  the  abdominal 
30 


466  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

organs  and  the  head  are  more  affected  than  those  of  the  extremities. 
This  widening  of  the  vessels  might  be  produced  either  by  depression 
of  the  vaso-constrictor  centre,  or  by  depression  of  the  nerve  ends  and 

jnuscle  of  the  arterioles  and  as  a  matter  of  fact  each  of  these  explana- 
tions has" '*Gad  its  'supporters,  "but  the  latter,  is  now  almost  universally 
held  to  be  the  correct  one.  Stimulation  of  a  constrictor  nerve  such  as 
the  splanchnic  still  produces  some  rise  in  the  blood-pressure,  so  that 
the  nerve  terminations  seem  to  be  intact,  and  the jseatof  action  of  amyl 

.nitrite  is  therefore  held  to  be  the  unstriated  muscle  of  the  arteries  and 
veins.  No  satisfactory  explanation  has  been  offered  for  the  fact  that 
in  the  skin  only  the  vessels  of  the  head  and  neck  should  be  dilated, 
but  other  facts  seem  to  indicate  that  these  vessels  occupy  an  exceptional 
position  as  regards  their  in  nervation  and  their  reactions  to  drugs. 
Darwin  was  the  first  to  point  out  that  the  blush  of  amyl  nitrite  corre- 
sponds in  extent  with  the  blush  produced  by  emotion.  Even  in  the 
frog  the  arterioles  of  the  tongue  are  said  to  dilate  more  than  those  of  the 
mesentery  and  the  web  after  the  application  of  amyl  nitrite.  The  vaso- 
constrictor centre  is  often  said  to  be  depressed  by  amyl  nitrite,  and 
this  may  possibly  be  true,  though  this  central  action  must  be  quite  in- 
significant compared  with  that  on  the  arterial  walls,  and  has  never 
been  demonstrated  even  by  the  most  careful  and  ingenious  methods  of 
experimentation.  The  direct  action  on  the  vessel  walls  may  be  easily 
shown  by  passing  blood  into  the  artery  of  the  amputated  extremity  of 
an  animal,  and  measuring  the  amount  coming  from  the  vein.  If  a  few 
drops  of  amyl  nitrite  be  added  to  the  perfused  blood,  the  outflow  from 
the  vein  is  greatly  increased,  although  here  no  nervous  mechanism  can 
be  concerned. 

The  acceleration  of  the  pulse  is  more  marked  in  man  and  the  dog 
than  in  other  animals,  and  seems  due  to  a  depression  oTthe  inhibitory 
centre  in  the  medulla  omongata,  though  several  authors  consider  that 

:^ajfeeble,  direct   action  on  the  Heart  is'  alscTpresent'." "TJie^cpronary 

arteries"  of  the  heart  are  dilated  along  witntKose~of  other  parts  of 
the  body. 

"""Large  quantities  of  amyl  nitrite  slow  and  weaken  the  contractions 
of  the  heart,  owing  to  a  direct  depressing  action  on  the  muscle.  In 
the  frog,  the  heart  is  usually  slowed  from  the  beginning  of  the  appli- 
cation. 

The  Respiration  is  generally  accelerated,  and  at  the  same  time  ren- 
dered deeper  by  amyl  nitrite.  Sot  infrequently  the  breath  is  held  at 
first,  owing  to  a  reflex  from  the  nasal  mucous  membrane,  but  this  is 
not  so  marked  as  in  the  inhalation  of  more  irritant  vapors,  such  as 
chloroform  or  ether.  The  acceleration  seems  due  to  a  direct  action, on 
the  respiratory  centre  in  the  medulla.  IfTffer  long  inhalation  the  res- 
piration becomes  slower  and  shallower  from  depression  of  the  centre, 
and  in  animals  death  occurs  from  its  complete  paralysis.  The  dilata- 
tion of  the  systemic  arterioles  permits  the  accumulation  of  blood  on  the 
venous  side  of  the  circulation,  and  this  in  turn  leads  to  the  amount  of 


THE  NITRITES. 


467 


FIG.  48. 


blood  in  the  lungs  being  augmented  ;  the  walls  of  the  pulmonary  ves- 
sels are  scarcely  affected  by  the  nitrites  directly. 

The  Kidneys  are  not  much  affected  by  this  series  ;  occasionally  a 
slight  increase  in  the  urine  is  observed,  at  other  times  a  decrease,  and 
after  large  quantities  anuria  may  occur.  The  changes  are  evidently 
due  to  the  changes  in  the  calibre  of  the  renal  vessels.  A  small  quan- 
tity may  widen  them  when  they  are  too  contracted  to  allow  of  the 
maximal  secretion,  while  on  the  other  hand,  if  the  normal  calibre  is 
the  optimal,  a  nitrite  may  lessen  the  secretion  by  lowering  the  general 
blood-pressure.  When  large  quantities  lower  the  pressure,  they  in- 
evitably lead  to  a  lessened  activity  of  the  renal  epithelium,  which  may 
result  in  complete  anuria. 

Small  quantities  of  amyl  nitrite  seem  to  have  no  action  whatsoever  on 
the  higher  parts  of  the  Central  Nervous  System. 
The  throbbing  in  the  head  and  slight  confusion 
are  evidently  due  to  the  dilatation  of  the  ves- 
sels, in  which  the  brain  circulation  is  involved 
as  well  as  that  of  the  rest  of  the  body.  The 
sight  is  curiously  affected  in  some  people,  for 
when  a  dark  object  on  a  white  background  is 
looked  at,  it  seems  surrounded  by  a  yellow 
ring  and  that  again  by  a  blue  one.  In  the 
beginning  the  medullary  centres  may  be  acted 
on  reflexly  from  irritation  of  the  nasal  sensory 
terminations;  the  respiration  is  inhibited,  while 
the  blood-pressure  may  rise  and  the  heart  be 
slowed  from  reflex  action  on  the  inhibitory  and 
vaso-constrictor  centres  respectively.  After- 
wards, the  respiratory  centre  seems  to  be  stim- 
ulated, the  inhibitory  is  depressed,  while  the 
vaso-motor  is  practically  unaffected.  The  spinal 
cord  is  not  acted  on  in  mammals,  but  is  de- 

pressed  in  the  frog.  covery.     The  whole  tracing  oc- 

cupied some  six  minutes.     The 

After  larger  quantities  convulsions  are  often   rapid  fan  of  pressure  is  followed 

!  j  i  „.  ,        ,         .     .  by  an  almost  equally  rapid  re- 

observea  ;   these  seem  to  be  ot  cerebral  origin,    turn  to  normal.    (CASH&DON- 
and  are  probably  due  to  direct  action  on  the 

nerve  cells,  and  not  to  the  circulatory  changes,  although  some  authors 
attribute  them  to  anaemia  of  the  brain. 

The  Peripheral  Nerves  and  the  Muscles  are  unaffected  by  the  inhala- 
tion of  amyl  nitrite,  but  when  the  frog's  muscles  are  exposed  to  the 
direct  action  of  the  vapor,  they  undergo  a  slow  passive  shortening  and 
rigor,  and  on  periodical  stimulation  the  contractions  become  rapidly 
weaker,  until  finally  no  response  is  made  to  the  electric  shock.  In- 
voluntary muscle  is  more  easily  affected  than  striated  fibres,  as  has 
been  shown  by  the  behavior  of  the  intestine  and  ureters,  but  even  these 
seem  less  readily  paralyzed  than  the  muscle  of  the  vessel  walls,  the  de- 
pression and  paralysis  of  which  lead  to  the  fall  in  the  arterial  tension, 


Blood-pressure  under  amyi  ni- 


468  ORGANIC  DRUGS    ACTING  AFTER    ABSORPTION, 

as  has  been  already  stated.  The  nerve  terminations  seem  to  be  un- 
affected even  by  very  large  quantities,  so  that  as  long  as  a  contraction 
of  the  muscles  can  be  elicited  by  direct  stimulation,  it  follows  also  on 
stimulation  of  the  motor  nerve,  and  the  vagus  terminations  in  the  heart 
can  transmit  impulses  as  long  as  the  heart  continues  to  beat.  The 
Temperature  is  somewhat  lowered  by  the  nitrite  series,  owing  to  the 
dilatation  of  the  skin  vessels,  but  this  fall  is  very  insignificant. 

Amyl  nitrite  causes  the  Blood  to  assume  a  dark  chocolate  color, 
both  in  the  body  and  in  the  test-tube.  The  color  is  due  not  to  any 
compound  formed  by  the  nitrites,  but  to  their  changing  the  haemoglo- 
bin to  methsemoglobin  and  nitric-oxide-hsemoglobin  compounds  in  which 
the  oxygen  is  attached  much  more  firmly  than  in  oxyhaemoglobin,  and 
which  differ  from  it  in  the  absorption  bands  seen  in  the  spectrum. 
This  change  in  the  haemoglobin  does  not  entail  the  destruction  of  the 
red  corpuscles,  and  the  compounds  are  eventually  reduced  by  the  tissues, 
although  the  reduction  progresses  much  more  slowly  than  that  of  ordi- 
nary oxy haemoglobin.  In  man,  usually  very  little  of  the  haemoglobin 
is  thus  transformed,  and  even  after  large  quantities  have  been  inhaled 
no  abnormal  coloration  of  the  blood  is  noticeable,  but  it  has  been  de- 
monstrated recently  that  the  alteration  of  the  haemoglobin  is  the  cause 
of  death  in  some  animals,  through  the  blood  becoming  incapable  of 
carrying  oxygen  to  the  tissues.  If,  however,  asphyxia  be  prevented 
by  the  inhalation  of  oxygen  under  pressure,  the  tissues  themselves  are 
eventually  acted  on.  The  formation  of  methaemoglobin  does  not  seem 
to  bear  any  relation  to  the  action  of  the  nitrites  on  the  vessel  walls. 

Excretion.  —  After  absorption  into  the  blood,  amyl  nitrite  seems  to 
break  up  with  the  formation  of  nitrites  of  the  alkalies.  These  undergo 
partial  oxidation  and  appear  in  the  urine  in  the  form  of  nitrates  and 
nitrites,  but  the  quantity  of  these  excreted  is  never  equal  to  the  nitrite 
absorbed,  so  that  it  seems  probable  that  some  part  undergoes  still  fur- 
ther change  and  appears  as  one  of  the  normal  excretions.  The  amyl 
disappears,  and  is  probably  oxidized  completely,  although  some  may 
appear  in  the  breath. 

Nitrite  of  amyl  given  by  the  stomach  is  very  much  less  active  than 
when  inhaled,  as  the  nitrous  acid  is  freed  by  the  gastric  juice  and  im- 
mediately decomposes.  When  injected  subcutaneonsly  it  acts  much 
more  slowly  and  weakly  than  when  absorbed  by  the  lungs,  and  gen- 
erally gives  rise  to  glycosuria  and  slight  diuresis.  No  satisfactory 
explanation  of  this  fact  has  been  given,  but  it  is  possible  that  the 
formation  of  methsemoglobin  may  cause  partial  asphyxiation  of  the 
tissues,  and  thus  cause  the  formation  of  excess  of  lactic  acid  and  gly- 
cosuria. 

The  pharmacopoeial  amyl  nitrite,  with  which  most  of  the  experi- 
ments have  been  performed  on  which  the  above  description  is  based, 
is  not  a  pure  substance,  but  consists  of  the  nitrites  of  two  different 
amyls  —  a-amyl  and  /9-amyl  —  along  with  isobutyl,  ethyl,  and  propyl 
nitrites.  A  number  of  the  pure  nitrites  have  been  examined  by  Cash 
and  Dunstan,  who  find  that  in  general  features  they  resemble  each 


THE  NITRITES.  469 

other  closely.  The  more  unstable  the  compound,  the  more  rapidly 
does  the  fall  in  blood-pressure  occur,  while  the  less  easily  decomposed 
compounds  are  somewhat  slower  in  their  action,  but  cause  depression 
of  the  blood -pressure  for  a  much  longer  time.  The  acceleration  of 
the  heart  and  the  extent  of  the  rigor  produced  in  the  frog's  muscle  de- 
pend also  on  the  rapidity  of  the  disintegration  of  the  nitrite  compound, 
and  therefore  are  parallel  to  the  fall  in  the  blood-pressure. 

The  Nitrites  of  Potassium  and  Sodium  act  very  similarly  to  those  of 
the  alkyls.  They  seem  to  have  a  more  powerful  action  on  muscular 
tissue,  however,  at  any  rate  in  the  frog,  for  the  muscles  are  paralyzed 
before  the  spinal  cord,  while  after  amyl  nitrate  the  reverse  is  the  case. 
They  are  administered  by  the  stomach,  and  therefore  act  more  slowly 
than  amyl  nitrite,  but  their  effects  last  much  longer.  The  gastric  juice 
liberates  part  of  the  nitrous  acid  before  absorption  can  occur,  and  it  is 
immediately  decomposed  and  often  causes  some  eructation.  The  nitric 
acid  formed  from  it  may  also  give  rise  to  irritation  of  the  gastro-in- 
testinal  mucous  membrane.  The  nitrite  absorbed  is  excreted  as  nitrate 

FIG.  49. 

5    10       20       30       40       50      1  hr.     |          _          _          ,          |      2  hrs.     t          |    2>f  hrs.  ( 


— A 

Diagram  to  illustrate  the  intensity  and  duration  of  the  action  of  the  members  of  the  nitrite  series. 
The  extent  of  the  fall  of  pressure  is  measured  along  the  vertical,  the  duration  along  the  horizontal 
line.  A,  amyl  nitrite,  ethyl  nitrite,  etc.;  B,  nitroglyceriu  ;  C,  sodium  nitrite ;  I),  erythrol  tetranitrate. 
The  greatest  reduction  occurs  in  A,  but  it  passes  off  for  the  most  part  in  5  minutes  and  entirely  in  20. 
Nitroglycerin  acts  more  rapidly  than  the  last  two,  and  its  effects  continue  almost  as  Jong  as  those  of 
sodium  nitrite.  Erythrol  tetranitrate  only  exerts  its  full  effect  after  the  action  of  the  others  has 
passed  off".  (After  BRADBURY.  ) 

in  the  urine,  although  some  of  it  may  remain  unoxidized.  The  metal- 
lic nitrites  do  not  as  a  rule  cause  so  much  headache  and  flushing  of 
the  face  and  neck  as  the  alkyl  compounds. 

Nitroglycerin  produces  the  same  effects  as  the  other  members  of 
this  series,  but  acts  much  more  powerfully  than  either  the  metallic  or 
alkyl  nitrites.  It  presents  some  minor  points  of  difference,  as  in  pro- 
ducing convulsions  in  the  frog  and  in  some  mammals  when  given  in 
very  large  quantities,  and  in  causing  more  severe  headache  in  man.  Il 
is  not  decomposed  in  the  stomach,  but  on  reaching  an  alkaline  fluid, 
such  as  the  blood,  at  once  breaks  up  into  glycerin,  nitrites  and  nitrates, 
in  the  proportion  of  two  parts  of  the  former  salt  to  one  of  the  latter. 
Its  action  commences  very  soon  after  its  administration,  and  lasts 
much  longer  than  that  of  amyl  nitrite.  The  explanation  of  its  greater 
activity  may  be  that  it  is  absorbed  unchanged,  but  is  then  broken 
up  at  once,  while  the  metallic  nitrites  are  decomposed  in  the  stomach 
and  much  of  the  nitrous  acid  is  lost. 

The  convulsions  are  probably  due  to  the  whole  molecule  of  nitro- 


470  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

glycerin,  which  may  perhaps  be  decomposed  more  slowly  in  some 
animals  than  in  others.  Nitroglycerin  is  not  wholly  broken  up  in 
the  human  body,  however,  for  it  has  been  found  in  the  urine,  and  the 
headache  which  so  frequently  follows  its  administration  in  man,  has 
been  ascribed  to  the  undecomposed  molecule,  and  not  to  the  nitrite 
constituent.  It  is  generally  supposed  to  be  extremely  poisonous, 
and  is  prescribed  in  exceedingly  minute  doses,  but  it  has  been  shown 
that  while  very  small  quantities  are  sufficient  to  produce  therapeutic 
effects  in  man,  the  toxic  dose  is  enormous  in  animals. 

Several  other  organic  nitrates  have  also  been  found  to  reduce  the 
blood-pressure,  and  to  cause  the  formation  of  methsemoglobin,  but  their 
decomposition  proceeds  much  more  slowly  than  that  of  nitroglycerin, 
and  they  have  not  been  much  used  in  therapeutics.  Erythrol  tetrani- 
trate  and  mannitol  hexanitrate  act  more  slowly,  and  the  fall  of  pres- 
sure is  more  gradual,  and  lasts  longer  than  under  any  others  of  the 
series. 

PREPARATIONS. 

AMYL  NITRIS  (B.  P.),  AMYLIS  NITRIS  (U.  S.  P.),  a  yellow,  very  volatile 
fluid,  with  a  strong,  fruity  odor,  soluble  in  alcohol  and  ether,  but  rapidly  decom- 
posed by  water.  2-5  drops  are  poured  on  a  handkerchief  and  inhaled.  A  con- 
venient preparation  is  the  arnyl  nitrite  ''pearls,"  which  are  thin  glass  capsules, 
each  containing  a  dose  of  the  remedy,  and  one  of  which  is  broken  in  the  hand- 
kerchief when  necessary.  Arnyl  nitrite  is  liable  to  decompose  when  kept  long, 
and  ought  to  be  used  only  when  recently  prepared. 

SPIRITUS  GLYCERYLIS  NITRATIS.(U.  S.  P.),  LIQUOR  TRINITRINI  (B.  P.),  is 
a  1  per  cent,  alcoholic  solution  of  nitroglycerin.  0.03-0.2  c.c.  (£-4  mins.). 

TABELL^:  TRINITRINI  (B.  P.),  or  nitroglycerin  tablets,  are  formed  of  choco- 
late, and  contain  each  T^  gr.  of  nitroglycerin.  1-2  tablets.  Nitroglycerin  is 
much  more  liable  to  decompose  in  tablets  than  in  the  alcoholic  solution,  and  the 
latter  ought  to  be  preferred  in  therapeutics  ;  even  the  alcoholic  solution  should 
not  be  kept  too  long. 

Liquor  Ethyl  Nitritis  (B.  P.),  a  solution  in  alcohol  and  glycerin  of  ethyl 
nitrite  (2J-3  per  cent.),  forming  a  limpid  liquid  of  apple-like  odor  and  taste. 
20-60  mins. 

Sodii  Nitris  (U.  S.  P.,  B.  P.)  (NaNO2),  0.05-0.1  G.  (1-2  grs.).  It  may  be 
prescribed  in  tablets  or  in  solution. 

SPIRITUS  ^ETHERIS  NITROSI  (U.  S.  P.,  B.  P.),  sweet  spirits  of  nitre,  con- 
tains only  traces  of  ethyl  nitrite,  along  with  ether  and  aldehyde  in  alcoholic 
solution.  When  freshly  prepared  it  acts  like  the  other  nitrites,  but  when 
prescribed  along  with  water,  as  is  usually  the  case,  the  nitrite  escapes 
rapidly,  and  it  has  little  effect  except  from  the  ether  and  alcohol.  1-5  c.c. 
(20-90  mins.). 

Nonofficial. 

Erythrol  tetranitrate  (CH2ONO2(CHONO2)2CH2ONO2)  is  a  solid,  and  is 
recommended  in  doses  of  0.05  G.  (1  gr.),  in  pills,  tablets  or  alcoholic  solu- 
tion. Like  nitroglycerin,  it  is  a  dangerous  explosive,  and  one  fatality  has 
already  occurred  in  forming  it  into  pharmaceutical  preparations. 

Therapeutic  Uses.  —  The  nitrites  were  introduced  into  therapeutics 
by  Brunton,  who  advised  their  use  in  angina  pectoris  to  relieve^ 
sj^asm  of  the  arteries.  They  are  certainly  the  most  powerfuT  depres- 
sants oi  the  blood-pressure  known,  and  may  be  used  in  all  cases  where 
this  appears  abnormally  high.  For  rapid  transient  effects  nitrite  of 
amyl  seems  specially  indicated,  while  nitroglycerin  and  nitrite  of  so- 


THE  NITRITES.  471 

dinm  are  more  suited  to  produce  a  depression  of  some  duration.  Thus 
during  the  attack  of  angina  pectoris,  amyl  nitrite  is  often  found  to  give 
instant  relief,  but  if  nitrite  of  soda  is  administered  every  4-6  hours,  no 
attack  may  occur.  The  disadvantage  of  the  metallic  nitrites  is  the  fre- 
quent eructation  they  produce,  while  nitroglycerin  often  causes  severe 
headache,  which,  however,  disappears  in  some  cases  after  repeated  use. 

Besides  in  angina  pectoris,  the  nitrite  series  may  be  used  in  any  con- 
dition in  which  it  is  supposed  that  the  arterial  tension  may  be  lowered 
with  benefit  to  the  economy.  Thus  nitroglycerin  has  been  advised 
in  heart  disease  and  has  accordingly  been  placed  by  some  among  the 
heterogeneous  group  of  "  Cardiac  tonics  or  stimulants."  Its  beneficial 
effects  are  not  due  to  any  direct  action  on  the  heart,  but  to  its  decreas- 
ing the  resistance  against  which  the  systole  is  performed.  In  this  way 
the  contraction  of  the  ventricle  is  rendered  more  complete,  and  the 
output  of  the  heart  may  be  increased.  In  weak  hearts  struggling 
against  a  high  aortic  resistance,  this  relief  may  be  followed  by  marked 
benefit,  and  for  this  reason  nitrite  preparations  (nitroglycerin)  are  often 
prescribed  in  chronic  Bright' s  disease.  Digitalis  causes  a  contraction  of 
the  peripheral  arterioles  along  with  its  proper  cardiac  action,  and  the 
addition  of  nitrite  may  be  advisable  in  some  cases  in  order  to  neutralize 
this  peripheral  action.  In  those  cases  the  nitrite  of  soda  or  nitrogly- 
cerin is  of  course  preferable  to  amyl  nitrite,  whose  action  is  too  transient. 
(See  Digitalis,  page  455.)  Amyl  nitrite  has  been  advised  in  accidents 
during  chloroform  anesthesia  on  the  theory  that  it  would  benefit  the 
circulation  ;  but,  as  a  matter  of  fact,  it  would  appear  strongly  contra- 
indicated  in  those  cases  in  which  it  is  true  that  the  heart  is  extremely 
depressed,  but  in  which  the  arterial  tension  is  practically  zero.  Its  use  is 
especially  irrational  if,  as  has  been  suggested,  the  failure  of  the  respira- 
tion is  partly  due  to  anaemia  of  the  central  nervous  system.  The  cases 
iu  which  recovery  has  occurred  after  this  measure  may,  in  fact,  be  said  to 
have  recovered  not  owing  to,  but  in  spite  of  the  use  of  amyl  nitrite. 

In  very  advanced  degeneration  of  the  cardiac  muscle  fibre,  the  ad- 
mi  nistrationofaniyT  nitrite  is  distinctly  contrainclicated,  for  the  blood- 
pressure  is  low  and  any  further  reduction  may  lead  to  syncope  from 
anemia  of  the  brain,  and  to  still  greater  weakness  of  the  heart  from 
the  low  pressure  in  the  coronary  arteries  lessening  its  nutrition. 

Nitrite  of  amyl  has  been  used  largely  in  asthma  and  in  cardiac 
dyspnoea.  Its  action  is  often  beneficial  and  has  been  attributed  to  its 
depressing  the  bronchial  muscles,  which  are  supposed  to  be  in  a  con- 
dition of  spasmodic  contraction  in  asthma.  In  the  cardiac  cases  its 

*.»«M«MMMMMMMB4MaMMaiNM*!*  i-i  ..         i  •  j.1 

action  in  removing  the  dyspnoea  may  be  due  to  its  lowering  the  pres- 
sure in  the  systemic  arteries  and  thus  relieving  the  heart. 

In  some  cases  of  headache,  nitrite  of  amyl  is  of  marked  benefit, 
while  in  others  it  aggravates  the  condition.  This  is  perfectly  intel- 
ligible, as  some  forms  of  headache  may  be  due  to  constriction  of  the 
arterioles  while  others  are  accompanied  by  a  congested  condition  of 
the  vessels  of  the  head. 

From  spasm  oFthe  circulatory  organs,  the  use  of  nitrite  of  amyl 


472  ORGANIC  DRUGS  ACTING   AFTER  ABSORPTION. 

has  been  extended  to  other  forms  of  spasmodic  seizures,  such  as  epi- 
lepsy. It  seems  to  be  of  little  or  no  value,  as  indeed  might  be  ex- 
pected from  its  pharmacological  action.  In  some  cases  it  even  seems 
to  increase  the  tendency  to  convulsions. 

Sweet  spirits  of  nitre  has  long  enjoyed  a  popular  reputation  as  a 
diaphoretic  and  diuretic.  It  seems  to  have  little  action  either  on  the 
kidneys  or  the  sweat  glands,  and  might  be  discarded  from  the  phar- 
macopoeia without  loss.  It  is  of  more  value  as  a  carminative  and 
flavor  than  for  any  other  purpose. 

BIBLIOGRAPHY. 

Brunton.  Arbeiten  aus  der  pliysiolog.  Anstalt,  zu  Leipzig,  iv.,  p.  101,  and  Journ, 
of  Anat.  and  Phys.,  v.,  p.  92. 

Wood.     Amer.  Journ.  of  Med.  Sciences,  Ixi.,  p.  422. 

Atkinson.     Journ.  of  Anat.  u.  Phys.,  xxii.,  p.  225. 

Mayer  u.  Friedrich.     Arch.  f.  exp.  Path.  u.  Pharra.,  v.,  p.  55. 

Hay.     Practitioner,  xxx.,  pp.  179-321. 

Leech.     British  Medical  Journal,  1893,  Vols.  i.,  p.  1305  and  ii.,  p.  4. 

Cash  and  Dunstan.     Phil.  Trans,  of  the  Royal  Soc.,  clxxxiv.,  B.,  p.  505. 

Gamgee.     Ibid.,  clviii.,  p.  589. 

Giacosa.     Ztschr.  f.  physiolog.  Chemie,  iii.,  p.  54. 

Mitchell  and  Reichert.     Amer.  Journ.  of  the  Medical  Sciences,  Ixxx.,  p.  158. 

Haldane,  Makgill  and  Mavrogordato.     Journal  of  Physiology,  xxi.,  p.  160. 

Schadow.     Arch.  f.  exp.  Path.  u.  Pharm.,  vi.,  194. 

Filehne.     Arch.  f.  Anat.  u.  Phys.,  1879,  p.  385. 

Marshall.     Jour,  of  Phys.,  xxii.,  p.  1. 

Bradbury.     Brit.  Med.  Journ.,  1895,  ii.,  p.  1213. 

C.  Rosenthal.     Archiv  f.  [Anat,  u.]  Phys.,  1888,  p.  29. 

W.  Rosenthal.     Ibid.,  1893.     Supplement,  p.  240. 

Laws.     Journ.  of  Amer.  Med.  Ass.,  xxxi.,  p.  793. 

Winkler.     Ztschr.  f.'klin.  Med.,  xxxv.,  p.  213  ;   xxxvi.,  pp.  30,  138. 

XXXI.     ERGOT. 

Ergot  is  a  parasitic  fungus  (Claviceps  purpurea)  which  grows  on  the 
rye  (Secale  cerealej  and  occasionally  ou  other  kinds  of  grain,  more 
rarely  on  other  plants.  It  is  of  great  importance  in  therapeutics  and 
also  in  toxicology,  as  the  use  of  bread  and  meal  containing  it  has  fre- 
quently given  rise  to  widespread  epidemics.  In  these  the  chief  symp- 
toms consisted  in  gangrene  of  the  limbs  or  in  convulsive  movements 
and  contractures. 

The  chemistry  of  ergot  is  still  in  an  unsatisfactory  condition,  as  its  active 
principles  seem  to  be  peculiarly  unstable,  and  are  decomposed  by  compara- 
tively weak  reagents.  A  large  number  of  imperfectly  isolated  bodies  have 
been  described  as  occurring  in  it,  but  the  first  approach  to  a  successful  treat- 
ment of  the  subject  was  made  by  Kobert  in  1884.  He  described  three  bodies 
as  involved  in  the  action  of  ergot,  the  first,  Ergotinic  Acid,  a  nitrogenous 
acid  of  glucosidal  nature,  the  second,  Cornutine,  an  alkaloid,  and  the  third, 
Sphacelinic  Acid,  a  resinous  acid  which  contains  no  nitrogen.  Various  other 
bases  have  been  observed  in  ergot  besides  cornutine,  but  most  of  them  are 
entirely  inert,  and  the  others  may  owe  their  action  to  the  presence  of  one  or 
more  of  these  three  bodies,  or  may  perhaps  be  identical  with  cornutine.  It 
must  be  added  that  Kobert  did  not  succeed  in  isolating  completely  any  of 
these  three  poisons,  but  he  was  able  to  show  that,  while  ergotinic  acid  be- 
haves in  the  same  way  as  the  members  of  the  sapotoxin  series,  cornutine 


ERGOT.  473 

stimulates  the  central  nervous  system  strongly  and  produces  convulsions,  while 
sphacelinic  acid  induces  gangrene  in  animals. 

Jacobj  has  recently  stated  that  the  action  of  sphacelinic  acid  is  due  to  a 
very  poisonous  resinous  body,  Sphacelotoxin,  which  seems  to  be  capable  of 
entering  into  loose  combinations  with  various  other  constituents  of  ergot. 
He  succeeded  in  isolating  two  such  compounds,  one  of  which,  Chrysotoxin 
proved  to  be  a  combination  of  sphacelotoxin  with  the  weakly  acid,  inactive 
body,  Ergochrysin,  the  other  of  which  Secalintoxin,  was  a  similar  compound 
of  sphacelotoxin  and  an  alkaloid,  Secaline.  Sphacelotoxin  he  found  to  be  a 
very  unstable  compound,  which  kept  better  when  in  the  form  of  chrysotoxin. 

The  action  of  ergot  as  known  at  present  is  therefore  a  complex 
which  may  be  analyzed  into  three  factors  :  1.  That  due  to  one  or  more 
bodies  somewhat  resembling  sapotoxin  in  action  and  contained  in  an 
impure  form  in  the  ergotinic  acid  of  Kobert.  2.  That  due  to  one  or 
more  convulsive  poisons  contained  in  the  cornutine  of  Kobert,  and  3, 
that  due  to  a  gangrene-producing  poison,  which  is  contained  in  the  spha- 
celinic acid  of  Kobert,  and  has  been  termed  sphacelotoxin  by  Jacobj. 

While  Cornutine  is  not  a  pure  principle  and  its  effects  may  be  due 
to  the  interaction  of  several  poisons,  the  train  of  symptoms  is  per- 
fectly distinct  from  those  induced  by  the  other  constituents  of  ergot, 
and  the  name  may  be  used  to  indicate  the  cause  of  these,  without  any 
definite  understanding  as  to  the  nature  of  the  body.  In  frogs  it 
induces  changes  in  the  skeletal  muscles  similar  to  those  described 
under  veratrine,  but,  unlike  the  latter,  does  not  affect  the  heart.  In 
both  frogs  and  mammals  convulsions  are  observed  and  seem  to  be  due 
to  stimulation  of  the  medulla  oblongata  and  the  basal  ganglia,  for  they 
disappear  in  the  frog  when  the  medulla  oblongata  is  destroyed,  and 
are  mainly  clonic  in  nature.  In  the  dog  the  symptoms  consist  of  rest- 
lessness, salivation,  vomiting,  and  purging.  The  pulse  is  slow  and 
irregular,  and  after  somewhat  larger  doses  clonic  convulsions  set  in 
with  intervals  of  depression.  The  respiration  ceases  during  one  of 
these,  while  the  heart  continues  to  beat  for  some  time. 

The  alteration  in  the  contraction  of  the  muscles  is  due  to  direct 
action  on  the  muscular  fibre,  similar  to  that  of  veratrine,  while  the  other 
symptoms,  like  those  from  picrotoxin,  are  caused  by  stimulation  of  the 
medulla  oblongata  and  the  nervous  centres  in  its  neighborhood.  The 
slow  rhythm  of  the  heart  can  be  removed  by  section  of  the  vagi,  and 
isjFerefor.e,diie,to  the  inhibitory  .centre.  The  vaso-constrictor  centre 
is  also  stimulated,  and  a  considerable  increase  in  the  arterial  pressure 
is  thus  caused,  although  this  may  be  concealed  by  the  slowness  of  the 
heart.  Neither  heart  nor  vessels  are  affected  directly.  The  nausea, 
salivation  and  vomiting  seem  to  be  the  result  of  medullary  action  also. 
Kobert  observed  that  both  stomach  and  bowel  contracted  powerfully 
under  cornutine,  and  that  wave-like  movements  occurred  at  the  same 
time  in  the  uterus,  whether  pregnant  or  not.  These  movements  were 
not  continuous,  but  resembled  peristaltic  contractions  and  did  not  tend 
to  empty  the  uterus.  They  were  not  produced  in  the  excised  organ 
when  it  was  perfused  with  blood  containing  cornutine,  and  he  there- 


474  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

fore  supposed  that  they  were  the  result  of  some  action  on  the  central 
nervous  system.  After  large  doses  of  cornutine  the  stimulation  of  the 
central  nervous  system  passes  into  paralysis  and  the  respiration  ceases. 

Sphacelotoxin  diifers  from  all  other  known  poisons  in  producing 
gangrene  of  various  organs,  more  especially  in  fowls  and  pigs. 

In  the  frog  the  symptoms  consist  of  depression  and  paralysis  of 
the  central  nervous  system.  In  most  mammals  (dogs,  cats,  rabbits, 
and  guinea-pigs)  the  chief  symptoms  arise  from  irritation  of  the  ali- 
mentary canal — salivation,  vomiting  and  some  purging — which  is 
induced  whether  the  drug  be  administered  by  the  mouth  or  subcuta- 
neously.  Later  some  signs  of  excitement  may  be  observed,  followed 
by  depression  and  weakness,  the  excitement  apparently  being  due  to 
cerebral  action.  Robert  found  numerous  extravasations  of  blood  in  the 
stomach,  intestine,  and  other  organs,  especially  when  the  drug  was 
given  for  some  time  and  chronic  poisoning  induced.  No  gangrene 
could  be  elicited  in  these  animals. 

In  fowls  a  much  more  characteristic  train  of  symptoms  is  found  to 
follow  the  administration  of  sphacelotoxin.  A  cock  soon  appears 
drowsy  and  somewhat  dyspnoeic,  and  the  comb  loses  its  bright  scarlet 
color  and  becomes  blue  and  cyanotic,  especially  at  the  tips.  Purging 
and  sometimes  vomiting  follow,  and  the  animal  has  often  great  diffi- 
culty in  preserving  its  balance,  swaying  to  and  fro  very  much  as  does 
a  patient  suffering  from  locomotor  ataxia.  After  small  doses  the 
symptoms  may  pass  off,  but  when  larger  quantities  have  been  injected, 
and  especially  if  chronic  poisoning  is  induced,  the  comb  becomes  dry 
and  hard  and  eventually  falls  off  without  any  haemorrhage.  The 
wattles,  tip  of  the  tongue,  wings  and  spurs  may  undergo  the  same 
process.  It  refuses  food,  loses  flesh  and  becomes  weak  and  somnolent, 
but  may  recover  if  the  treatment  be  stopped ;  otherwise  it  dies  of 
inanition  and  general  weakness.  The  vessels  of  the  comb  are  found 
to  be  filled  with  a  transparent  "  hyaline  "  mass  with  a  narrow  streak 
of  red  corpuscles  here  and  there,  and  it  is  evident  that  a  typical  dry 
gangrene  has  been  induced.  Marked  irritation  of  the  mucous  mem- 
brane of  the  crop,  stomach  and  bowel  is  present,  with  numerous  ex- 
travasations, frequently  with  circumscribed  areas  of  necrosis.  (Edema 
and  ecchymoses  are  often  met  with  in  the  subcutaneous  tissue  and  also 
in  the  internal  organs,  and  a  curious  substance  resembling  amyloid 
was  seen  in  the  liver  by  Griinfeld.  No  alteration  of  the  central  ner- 
vous system  has  been  detected  after  careful  examination.  In  pigs,  the 
ears  become  dark-colored  and  cyanotic  and  the  tips  undergo  dry 
gangrene  and  fall  off.  Gangrene  is  also  observed  in  the  extremities 
and  in  different  parts  of  the  skin  of  the  trunk,  and  hemorrhages  into 
internal  organs  occur,  especially  in  the  bowel. 

The  gangrene  appears  to  be  due  to  a  prolonged  contraction  of  the 
arterioles  shutting  off  the  blood  supply  of  the  parts  and  leading  to  a 
hyaline  formation  in  the  lumen  and  walls  of  the  arterioles,  which 
effectually  obstructs  the  circulation  after  the  muscular  coats  have 
relaxed.  The  constriction  of  the  arterioles  has  been  shown  to  occur  in 


ERGOT.  475 

animals  in  which  no  gangrene  follows,  but  is  probably  not  so  extreme 
in  these.  This  constriction  of  the  arterioles  of  course  induces  an 
increase  in  the  blood-pressure,  which  was  found  by  Robert  to  be  of 
considerable  extent,  while  Jacobj  found  it  less  marked.  Curiously 
enough,  the  blood-pressure  in  the  fowl  has  not  been  examined  under 
sphacelotoxin,  although  it  might  be  expected  to  be  more  augmented  in 
these  than  in  many  other  animals. 

Robert  supposed  that  the  arterioles  were  constricted  by  the  increased 
activity  of  the  vaso-motor  centre,  but  Jacobj  has  shown  that  there  is 
also  some  peripheral  action,  for  the  blood-pressure  rises  after  division 
of  the  spinal  cord,  and  the  flow  of  blood  through  an  excised  organ  is 
considerably  retarded  when  sphacelotoxin  is  added  to  it.  He  there- 
fore considers  that  the  muscular  wall  of  the  vessels  is  acted  on  directly, 
as  well  as  through  the  central  nervous  system. 

Jacobj  found  that  sphacelotoxin  often  induced  abortion  in  pregnant 
animals,  and  concludes  that  it  provokes  uterine  contractions,  which 
are  not  tetanic  in  nature,  but  which  rather  resemble  the  normal  peri- 
staltic contractions  of  the  uterus  during  labor.  These  wave-like  con- 
tractions move  the  foetus  towards  the  os  uteri,  and  eventually  cause  its 
expulsion.  He  found  that  abortion  could  be  induced  without  serious 
injury  to  either  parent  or  young.  The  contractions  of  the  uterus  may 
be  due  to  some  action  on  the  spinal  cord,  as  has  been  generally  believed, 
but  it  must  not  be  forgotten  that  the  uterus  is  capable  of  automatic 
movement  and  that  the  young  can  be  expelled  from  it  after  destruc- 
tion of  the  spinal  cord,  so  that  it  seems  not  unlikely  that  ergot  acts 
rather  on  the  uterine  fibres  directly  than  through  the  nervous  centres. 
This  uterine  action  is  elicited  in  animals  in  which  ergot  does  not  induce 
gangrene,  such  as  the  rabbit  and  cat.  Palm  has  recently  confirmed 
Jacobj's  results,  and  extended  them  by  showing  that  sphacelotoxin 
induces  contractions  of  the  uterus  in  patients  during  labor.  After 
small  doses  the  pains  resemble  those  occurring  naturally,  but  large 
quantities  cause  a  tetanic  contraction  of  the  uterus,  which  may  seriously 
injure  the  child. 

The  Ergotinic  Acid  of  Robert  seems  to  have  little  or  no  effect  when  given 
by  the  mouth,  but  induces  depression  and  paralysis  of  the  spinal  cord  when 
injected  subcutaneously  or  intravenously  in  frogs  and  mammals.  The  higher 
divisions  of  the  nervous  system  seem  less  readily  affected,  although  the 
brain  is  also  depressed,  and  unconsciousness  and  collapse  may  follow.  The 
blood-pressure  is  much  reduced  from  depression  of  the  vaso-motor  centre, 
while  the  heart  seems  comparatively  little  affected.  Death  occurs  from 
paralysis  of  the  respiratory  centre. 

In  addition  to  these  three  bodies  there  are  probably  other  active  principles 
contained  in  ergot,  for  some  preparations  of  the  drug  cause  very  distinct 
slowness  and  weakness  of  the  pulse,  which  does  not  seem  to  be  induced  by 
any  of  the  three  constituents  described  above.  None  of  the  principles  have  been 
extensively  used  in  medicine  except  in  impure  forms. 

Ergot  has  rarely  given  rise  to  Acute  Poisoning  in  Man,  but  in  several 
cases  in  which  it  was  taken  in  order  to  induce  abortion,  the  symptoms 
consisted  in  collapse,  with  a  weak,  rapid  pulse,  tingling,  itching  and 


476  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

coldness  of  the  skin,  unquenchable  thirst,  vomiting  and  diarrhoea, 
confusion  or  unconsciousness,  haemorrhages  from  the  uterus,  abortion, 
and  some  icterus.  Ecchymoses  were  found  in  the  subcutaneous  tissue 
and  in  many  internal  organs.  Somewhat  similar  symptoms  have  been 
produced  in  animals. 

Chronic  Poisoning  was  formerly  not  uncommon,  and  in  fact  frequently 
gave  rise  to  widespread  epidemics,  from  the  use  of  bread  containing  ergot 
after  poor  harvests  and  especially  in  wet  seasons.  Of  late  years  these 
epidemics  have  become  rare  except  in  Russia,  but  some  of  the  "  plagues  " 
of  mediaeval  Europe  may  have  been  due  to  ergot  poisoning. 

The  symptoms  of  ergotism  are  sharply  divided  into  two  groups, 
those  of  gangrene  and  those  of  nervous  disorders.  In  some  epidemics 
both  the  gangrenous  and  the  convulsive  forms  are  present,  but,  as  a 
general  rule,  one  is  much  more  prevalent  than  the  other,  at  one  time 
gangrene  being  almost  invariably  present,  while  in  another  epidemic, 
the  convulsive  type  is  the  more  common.  The  gangrene  is  generally 
developed  in  the  limbs,  especially  in  the  fingers  and  toes ;  sometimes 
the  whole  arm  or  leg  becomes  cold  and  anaesthetic,  dark  in  color,  and 
then  dry,  hard  and  shrunken,  and  falls  off  with  little  or  no  pain  and 
no  hemorrhage.  Symptoms  of  such  severity  are  rare,  however,  and 
in  milder  cases  only  the  skin  necroses.  Gangrene  of  internal  organs 
also  occurs,  resulting  in  cataract  in  the  lens  of  the  eye,  or  ulcers  in  the 
bowel  and  stomach,  and  sometimes  affecting  a  whole  organ  such  as  a 
lung  or  the  uterus.  Abortion  is  seldom  mentioned  in  the  accounts  of 
chronic  ergot  poisoning,  and  pregnancy  seems  in  many  cases  to  have 
run  its  ordinary  course.  Gangrenous  ergotism  is  evidently  due  to 
sphacelotoxin  causing  prolonged  contraction  of  the  vessels,  followed 
by  hyaline  thrombosis.  The  blood  vessels  in  man  therefore  seem  to 
be  acted  on  in  the  same  way  as  those  of  the  fowl  and  pig,  while  those 
of  the  other  mammals  escape. 

In  spasmodic  ergotism  the  first  symptoms  are  depression,  weakness 
and  drowsiness,  often  with  headache  and  giddiness,  painful  cramps  in 
the  limbs,  and  itching  and  formication  of  the  skin.  In  severe  cases 
paroxysmal  convulsions  set  in,  generally  clonic,  and  often  epileptiform, 
but  leaving  as  sequelae  contractures  in  the  limbs,  or  less  often  in  the 
trunk  muscles.  Some  intellectual  weakness  often  follows  recovery 
from  ergot  poisoning,  this  not  infrequently  amounting  to  complete 
dementia,  but  the  disease  was  immediately  fatal  in  a  large  proportion 
of  cases  in  earlier  times.  Cornutine  was  supposed  by  Kobert  to  be  the 
cause  of  the  convulsive  form  of  ergot  poisoning,  and  his  explanation 
has  been  generally  accepted,  although  it  is  not  without  difficulties, 
for  chronic  poisoning  with  cornutine  does  not  produce  any  symptoms 
whatever  in  animals,  unless  doses  sufficient  to  cause  acute  poisoning  are 
given.  On  the  other  hand,  fowls  poisoned  with  sphacelotoxin  suffer 
from  ataxia  and  other  nervous  symptoms,  so  that  it  is  probable  that 
other  factors  besides  cornutine  are  involved  in  the  production  of  these 
symptoms  in  epidemic  poisoning  and  the  entire  action  may  perhaps  be 
due  to  sphacelotoxin. 


ERGOT.  477 

The  accounts  of  different  observers  of  the  action  of  ergot  on  the  individual 
organs  present  great  discrepancies.  This  is  explained  by  the  difference  be- 
tween the  preparations  used  and  by  the  extreme  instability  of  the  more  active 
principles.  The  effects  on  the  circulation  are  especially  liable  to  vary,  for  in 
many  cases  the  heart  is  rendered  slow  and  weak,  sometimes  apparently  from 
cornutine  acting  on  the  vagus  centre,  at  other  times  from  some  unknown 
body  affecting  the  muscle  directly  ;  in  others  acceleration  of  the  heart  has 
been  observed.  Very  often  the  preparations  known  as  ergo  tin  are  stated  to 
cause  a  very  marked  fall  in  blood-pressure,  while  others  which  probably 
contain  larger  amounts  of  sphacelotoxin  and  cornutine  contract  the  arterioles 
and  increase  the  blood-pressure.  Further  dispute  has  arisen  as  to  whether 
this  effect  is  central  or  peripheral.  It  is  obviously  unprofitable  to  discuss 
these  questions,  however,  as  scarcely  any  two  of  the  investigators  have  used 
the  same  preparation,  and  there  is  no  means  of  judging  of  what  constituents 
their  drugs  were  composed. 

The  effects  of  ergot  and  its  preparations  on  the  Uterus  are  no  less  a 
matter  of  dispute.  Many  gynaecologists  consider  that  it  does  not  excite 
movements  in  the  uterus,  but  that  when  labor  has  commenced,  it  pro- 
longs the  contractions  and  may,  in  fact,  cause  a  continuous  contrac- 
tion (tetanus)  of  the  muscular  fibres,  which  delays  the  expulsion  of 
the  contents  and  imperils  the  life  of  both  mother  and  child.  On  the 
other  hand,  some  believe  that  ergot  induces  uterine  contractions  and 
strengthens  those  present  in  labor,  without  necessarily  hindering  the 
periodic  relaxation  of  the  muscle,  and  Jacobj's  and  Palm's  results  with 
sphacelotoxin  would  confirm  the  latter  view.  These  discrepancies  are 
undoubtedly  to  be  explained  by  the  fact  that  preparations  of  ergot  are 
very  often  employed  which  are  entirely  inert,  while  in  other  cases  effects 
have  been  credited  to  ergot  which  have  appeared  before  it  was  possible 
that  the  drug  was  absorbed.  The  action  of  ergot  on  the  uterus  is  not  suffi- 
ciently certain  to  permit  of  definite  statements,  but  it  seems  unquestion- 
able that  in  animals  it  produces  abortion,  and  must  therefore  induce  move- 
ments similar  to  those  occurring  in  normal  labor.  It  is  probable  that 
in  the  human  uterus  the  same  effect  is  induced,  while  the  so-called 
"  tetanus  uteri "  may  perhaps  be  explained  by  the  use  of  large  doses  or 
very  active  preparations.  It  may  very  well  happen  that  a  substance 
which  in  small  quantities  only  increases  the  irritability  of  the  muscle 
or  strengthens  the  normal  contractions,  may  induce  very  prolonged 
contractions  when  applied  in  larger  quantities  (compare  the  action  of 
digitalis  on  the  frog's  heart). 

Some  experiments  have  been  performed  to  find  whether  the  contrac- 
tions of  the  uterus  under  ergot  are  due  to  action  on  the  uterus  itself  or 
on  the  nervous  centres.  But  the  results  are  again  contradictory  and 
need  not  be  detailed. 

Robert  at  first  supposed  that  sphacelotoxin  was  the  more  important 
body  in  the  action  of  ergot  on  the  uterus,  and  this  view  has  been  held 
by  most  authors  since  then,  and  has  been  supported  in  particular  by 
Jacobj.  Of  late  years,  however,  Robert  has  come  to  regard  cornutine  as 
the  chief  factor  in  this  result,  although  there  seems  no  satisfactory  work, 
either  experimental  or  clinical,  in  support  of  his  more  recent  view. 

The  vomiting  and  diarrhoea  which  are  sometimes  observed  after 
ergot  may  be  of  central  origin,  but  are  generally  supposed  to  be  due  to 


478  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

direct  action  on  the  muscular  coats  of  the  stomach  and  intestines  sim- 
ilar to  that  described  by  some  authors  as  occurring  in  the  uterus. 

PREPARATIONS. 

U.  S.  P. — Ergota,  ergot  of  rye,  the  sclerotium  of  Claviceps  purpurea  re- 
placing the  grain  of  rye.  When  more  than  one  year  old  it  is  unfit  for  use. 

Extractum  Ergots,  0.2-1  G.  (3-15  grs.). 

FLUIDEXTRACTUM  ERGOT^E,  4-8  c.c.  (1-2  fl.  drs.). 

Vinum  Ergotse,  10-20  c.c.  (5-10  fl.  drs.). 

B.  P. — Ergota,  the  sclerotium  of  Claviceps  purpurea,  originating  in  the 
ovary  of  Secale  cereale.  20-60  grs. 

Extractum  Ergotse  (Ergotiu),  2-8  grs. 

EXTRACTUM  ERGOTS  LIQUIDUM,  10-30  mins. 

Tinctura  Ergotse  Ammoniata,  \— 1  fl.  dr. 

Infusum  Ergotse,  1-2  fl.  oz. 

INJECTIO  ERGOT.E  HYPODERMIC  A,  3-10  mins.  (subcutaneously).  The  in- 
jection ought  to  be  recently  prepared.  It  is  about  33  per  cent. 

The  fluid  or  liquid  extracts  and  the  hypodermic  injection  are  the  best  of 
the  preparations.  The  vinum  is  very  often  quite  inert,  and  the  extract  being 
prepared  from  the  fluid  extract  by  heat  is  liable  to  contain  less  of  the  un- 
stable active  constituents  than  the  latter.  A  very  large  number  of  prepa- 
rations, such  as  ergotin,  ergotinic  acid,  sclerotinic  acid,  cornutine,  etc. ,  are 
simply  more  or  less  purified  extracts  and  have  no  advantage  over  the  phar- 
macopceial  preparations  ;  in  fact  the  chemical  manipulations  through  which 
they  are  obtained  are  often  such  as  are  likely  to  remove,  or  render  inert,  the 
active  bodies  of  the  crude  drug. 

The  dose  of  the  preparations  of  ergot  is  exceedingly  variable,  as  a  quantity 
sufficient  to  induce  very  marked  effect  in  autumn,  may  be  found  entirely 
inert  in  the  following  spring.  Griinfeld,  in  fact,  states  that  in  March  and  April 
twelve  times  as  much  is  required  as  in  July  and  August,  and  that  in  May 
and  June  the  drug  is  entirely  without  effect  in  any  dose,  but  this  is  probably 
an  exaggeration,  unless  where  the  ergot  has  been  carelessly  stored.  Accord- 
ing to  Jacobj ,  the  pure  chrysotoxin  may  be  kept  for  years  without  deterior- 
ating. Sterilized  fluid  extract  is  said  to  keep  better  than  the  ordinary 
preparations,  but  the  whole  subject  requires  further  research. 

Therapeutic  Uses.  —  Ergot  is  used  very  largely  in  obstetrics  to  pro- 
mote the  contraction  of  the  uterus,  but  considerable  divergence  is  met 
with  in  the  views  of  different  authorities  as  to  the  special  indications 
for  its  exhibition.  Thus,  those  who  believe  that  ergot  increases  the 
irritability  of  the  uterus  and  produces  rhythmical  contraction  without 
tetanus,  advise  that  it  be  given  whenever  the  pains  seem  insufficient, 
and  more  especially  when  this  occurs  in  the  later  stages  of  labor. 
Others  are  possessed  with  perhaps  an  exaggerated  apprehension  of  the 
prolonged  uterine  contractions,  which  they  consider  delay  labor  and 
tend  to  cause  asphyxia  in  the  child,  and  therefore  advise  that  ergot  be 
used  only  to  preserve  the  uterus  in  a  contracted  condition  after  the 
child  and  placenta  have  been  expelled.  In  every  case  the  attendant 
should  of  course  satisfy  himself  before  giving  ergot  of  the  absence  of 
all  actual  impediments  to  the  passage  of  the  child,  such  as  contracted 
pelvis,  abnormal  presentation,  or  great  rigidity  of  the  soft  parts,  and 
when  it  is  administered  before  the  head  emerges,  the  dose  ought  to  be 
small,  as  otherwise  the  tonic  contraction  may  be  induced.  When  the 


ERGOT.  479 

head  is  about  to  emerge,  on  the  other  hand,  a  large  dose  may  be  given 
to  promote  the  permanent  contraction  of  the  uterus  and  thus  to  pre- 
vent post-partum  haemorrhage.  When  the  latter  has  once  set  in,  er- 
got is  of  less  immediate  service,  as  it  is  slowly  absorbed,  and  no  ef- 
fects follow  for  some  twenty  minutes  or  more.  Whenever  there  is  any 
reason  to  fear  that  weakness  of  the  uterine  contraction  and  haemor- 
rhage may  set  in  after  the  expulsion  of  the  child,  ergot  ought  to  be 
given  when  the  head  emerges,  and  many  gynecologists  recommend  this 
as  a  routine  treatment. 

Ergot  hinders  post-partum  hemorrhage,  chiefly  by  promoting  the 
contraction  of  the  uterus.  In  other  forms  of  hemorrhage  —  from  the 
stomach,  intestines,  kidneys,  lung  or  uterus  —  in  which  the  bleeding 
point  cannot  be  reached,  it  is  often  advocated  in  the  belief  that  it  con- 
tracts the  walls  of  the  vessels  and  thus  arrests  the  flow  of  blood. 
These  hemorrhages  so  often  cease  spontaneously  that  it  is  difficult  to 
estimate  the  value  of  any  remedy,  but  it  may  be  questioned  whether 
ergot  merits  its  reputation  in  these  cases.  Its  action  in  healthy  ani- 
mals certainly  indicates  that  the  contraction  of  the  vessels  is  confined 
to  certain  organs,  otherwise  there  would  be  a  more  distinct  increase  in 
the  blood-pressure.  And  there  is  no  reason  to  suppose  that  a  more 
intense  action  is  exerted  on  a  ruptured  vessel  than  on  the  uninjured 
ones  of  other  organs ;  but  unless  this  is  the  case  the  use  of  ergot  may 
be  rather  harmful  than  remedial,  for  any  increase  in  the  general  blood- 
pressure,  such  as  would  follow  the  contraction  of  the  vessels  through- 
out the  body,  must  increase  the  escape  of  blood  from  the  injured  ves- 
sel. In  these  cases,  as  in  labor,  the  fluid  extract  is  often  given  by  the 
mouth,  but  this  extract  or  the  special  preparation  of  the  B.  P.  is 
sometimes  injected  .with  the  hypodermic  needle.  It  is  irritant,  and 
ought  therefore  to  be  injected  deeply  into  the  muscle,  rather  than  into 
the  subcutaneous  tissues. 

The  effect  of  ergot  in  inducing  contraction  of  the  uterus  has  been 
used  in  the  treatment  of  subinvolution  and  of  myomata  of  that  organ ; 
the  involution  of  the  uterus  certainly  seems  to  be  favored  by  it, 
but  the  results  in  tumor  are  more  open  to  question.  In  any  case  the 
prolonged  treatment  of  this,  or  of  any  other  condition  with  ergot 
is  to  be  deprecated,  for  if  the  drug  is  active  at  all,  it  may  induce  gan- 
grene or  spasmodic  ergotism.  The  same  criticism  might  be  applied 
to  the  ergot  treatment  of  a  number  of  other  diseases,  such  as  aneurism, 
diabetes,  or  pneumonia ;  and  in  addition,  it  does  not  seem  to  have  any 
greater  effect  in  these  than  many  other  less  dangerous  remedies,  which 
have  been  equally  vaunted  as  specifics,  and  have  been  found  equally 
valueless. 

BIBLIOGRAPHY. 

Robert     Arch.  f.  exp.  Path.  u.  Pharra.,  xviii.,  p.  316. 

Griinfdd.     Arb.  a.  d.  pharmakol.  Institute  zu  Dorpat,  vii.,  p.  108;  xii.,  p.  295. 

Jacob}.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxix.,  p.  85. 

Houghton.     Therap.  Gazette,  1898,  p.  433. 

Walker.     Arch.  f.  Psychiatric,  xxv.,  p.  383. 

Jahrmdrker.     Ibid.,  xxxv.,  p.  109. 


480  ORGANIC  DRUGS  ACTING  AFTER  ABSORPTION. 

Palm.     Arch.  f.  Gynaekologie,  Ixvii. 
Santesson:     Skand.  Arch.  f.  Physiol.,  xiii.,  p.  107. 

The  earlier  literature  is  to  be  found  in  Griinfeld's  paper,  but  the  student  is  recom- 
mended to  read  the  above  papers  before  proceeding  to  the  earlier  work. 

TIstilagO  Maydis  (U.  S.  P.),  or  corn  smut,  a  fungus  growing  on  maize,  is 
entirely  different  from  ergot,  and,  according  to  Robert,  is  quite  inert.  It  has 
been  used  as  a  substitute  for  ergot,  on  the  supposition  that  it  would  resemble  it 
in  action  as  well  as  in  origin,  but  has  proved  quite  ineffective. 

Cotton-root  Bark  (Gossypii  Cortex  (U.  S.  P.))  has  been  used  by  the  Southern 
negroes  to  produce  abortion,  and  is  said  by  some  gynecologists  to  resemble  ergot 
in  action  on  the  uterus.  It  has  little  or  no  effect  on  animals,  except  in  enor- 
mous doses,  and  is  generally  stated  by  those  who  have  tested  it  to  be  entirely 
devoid  of  action  in  man. 


PART  III. 

COMBINATIONS   OF   THE   ALKALIES,  ALKALINE 
EARTHS,    ACIDS   AND   ALLIED   BODIES. 

SALT-ACTION. 

THE  action  of  most  of  the  substances  discussed  in  the  foregoing  pages 
may  be  best  explained  by  supposing  that  they  cause  some  change  in 
the  living  matter  of  one  or  more  organs  through  a  specific  chemical 
affinity  for  it.  Thus  strychnine  may  be  supposed  to  act  on  the  spinal 
cord  by  forming  a  chemical  compound  with  the  protoplasm  of  the 
nerve  cells,  while  prussic  acid  changes  protoplasm  generally,  through 
a  similar  affinity  for  it. 

Some  bodies,  on  the  other  hand,  seem  to  have  little  specific  affinity 
for  living  matter,  but  affect  it  largely  as  they  do  dead  colloid  sub- 
stances, through  changing  the  physical  properties  of  the  fluids  contained 
in  it  or  surrounding  it.  This  action  is  seen  best  in  the  effects  of  some 
of  the  salts  of  the  alkalies,  and  is  therefore  known  as  "  salt-action," 
although  it  is  not  confined  to  these,  but  is  shared  by  any  soluble, 
diffusible  body  which  can  circulate  in  the  tissues  in  sufficient  quantity. 
The  salts  of  strychnine  or  of  prussic  acid  are  undoubtedly  capable  of 
inducing  physical  changes  similar  to  those  observed  after  chloride  of 
sodium,  but  they  play  no  part  in  the  symptoms  induced  by  these 
poisons,  because  animals  die  from  the  specific  action  long  before  the 
quantity  necessary  to  induce  the  "  salt-action  "  can  be  absorbed.  In 
the  case  of  less  poisonous  organic  substances,  such  as  sugar  and  urea, 
however,  many  of  the  features  of  salt-action  may  be  observed. 

Much  light  has  been  thrown  on  the  nature  of  salt-action  by  the  re- 
cent advances  in  physical  chemistry,  which  have  shown  that  many  of 
the  changes  in  the  animal  body  are  analogous  to  those  observed  in  the 
chemical  laboratory.  When  an  aqueous  solution  of  sugar  or  salt  is 
carefully  poured  on  distilled  water,  so  that  two  layers  are  formed,  a 
process  of  Diffusion  commences,  the  dissolved  molecules  passing  through- 
out the  fluid  until  the  whole  becomes  homogeneous,  each  cubic  centi- 
metre containing  an  equal  number  of  molecules  of  sugar  or  salt.  If 
instead  of  distilled  water,  a  solution  of  another  salt  be  used,  the  same 
process  results,  the  two  bodies  diffusing  throughout  both  fluids  until 
these  become  homogeneous ;  and  if  the  fluids  be  separated  by  a  mem- 
brane which  offers  no  obstacle  to  the  penetration  of  the  water  and 
salts,  a  similar  interchange  occurs.  When  a  membrane  is  used  which 
does  not  allow  the  salt  to  pass  through  it,  a  different  result  is  observed ; 
31  481 


482  INORGANIC     SALTS,   ACIDS  AND  BASES. 

if  it  separates  salt  solution  from  pure  water,  the  latter  passes  through 
until  it  is  exhausted,  or  until  some  factor  such  as  hydrostatic  pressure 
puts  a  limit  to  further  movement.  This  is  readily  intelligible,  for  the 
pure  water  can  pass  without  hindrance  towards  the  salt,  but  having 
rendered  the  solution  more  dilute,  it  cannot  diffuse  in  the  opposite 
direction,  because  this  would  be  equivalent  to  forming  a  more  concen- 
trated solution  of  the  salt,  and  this  requires  the  expenditure  of  energy, 
such  as  heat,  while  in  the  case  in  point  there  is  no  energy  available  for 
this  purpose.  A  similar  result  is  obtained  if  the  membrane  separate 
solutions  of  a  non-permeating  and  of  a  permeating  salt,  the  latter 
passing  through  with  the  fluid  in  which  it  is  dissolved  until  some  ex- 
traneous factor  counterbalances  the  diffusion. 

The  resistance  offered  by  a  non-permeating  salt  to  the  passage  through 
the  membrane  of  the  fluid  in  which  it  is  dissolved  is  known  as  the  Osmotic 
Pressure  of  the  solution  and  varies  with  the  number  of  molecules  and 
ions  (see  page  484).  When  both  the  salts  in  solution  on  the  opposite 
sides  of  the  membrane  are  unable  to  penetrate  through  it,  the  move- 
ment of  the  fluid  is  determined  by  the  relative  osmotic  pressure  on  the 
two  sides,  water  tending  to  pass  from  the  solution  with  the  lower 
osmotic  pressure  (the  hypotonic  solution)  to  that  with  the  higher  (hyper- 
tonic)  until  an  equilibrium  is  established  by  the  osmotic  pressure  be- 
coming equal  on  the  two  sides,  when  the  solutions  are  said  to  be  isotonic. 
As  a  general  rule,  however,  membranes  are  partially  permeable  to  both 
salts,  and  the  movement  of  the  fluid  is  determined  by  the  relative 
osmotic  pressure  of  the  fluids  divided  by  the  rate  at  which  the  salts 
pass  through  the  membrane.  If  sufficient  time  is  allowed  to  elapse, 
the  two  solutions  will  become  identical  in  composition,  but  during  a 
short  period,  the  details  of  the  process  are  difficult  to  follow,  and  the 
complexity  is  infinitely  greater  when  instead  of  a  single  salt  on  each 
side  of  the  membrane  there  are  several  salts  each  differing  in  its  per- 
meability and  concentration.  The  direction  of  the  flow  is  then  deter- 
mined by  the  sum  of  the  osmotic  pressure  on  each  side  divided  by  the 
penetrating  power  of  each  individual  substance. 

In  the  animal  body  such  membranes  as  are  used  in  physical  experi- 
ments are  not  met  with,  but  the  cells  consist  of  colloid  substances  con- 
taining fluid  and  diffusible  bodies,  and  are  surrounded  by  liquids  which 
are  practically  salt  solutions  isotonic  with  the  contents  of  the  cells ; 
any  change  in  the  contents  of  the  cell  or  in  the  lymph  surrounding  it 
must  of  necessity  give  rise  to  a  certain  movement  of  the  fluids  in  the 
same  way  as  if  each  cell  were  surrounded  by  a  membrane.  All  the 
ceils  of  the  body  are  permeable  by  water,  and  a  dilution  of  the  fluids 
surrounding  them  is  therefore  followed  by  an  increase  in  their  fluid 
contents  and  swelling.  On  the  other  hand,  some  salts  seem  to  diffuse 
into  cells  practically  without  resistance,  while  others  fail  altogether  to 
do  so,  or  penetrate  only  very  slowly.  The  subject  has  been  investi- 
gated with  most  care  in  the  red  blood  cells,  which  are  found  to  be  pene- 
trated by  ammonium  chloride  and  some  other  salts,  while  they  are 
impermeable  by  sodium  chloride  and  the  other  salts  of  the  fixed 


SALT-ACTION.  483 

alkalies.  Accordingly,  when  the  red  blood  cells  are  surrounded  by  a 
solution  of  ammonium  chloride,  whatever  its  concentration,  their  fluid 
contents  are  increased ;  they  swell  up  and  eventually  lose  their  haemo- 
globin, exactly  as  if  they  had  been  placed  in  pure  water.  When 
they  are  placed  in  an  isotonic  solution  of  chloride  of  sodium,1  they 
remain  unchanged  in  size,  while  in  a  hypertonic  solution  their  fluid  dif- 
fuses out,  and  they  shrink ;  a  hypotonic  solution  acts  like  pure  water, 
the  osmotic  pressure  of  the  salts  in  the  corpuscles  overcoming  the 
smaller  osmotic  pressure  of  the  surrounding  fluid.  The  behavior  of 
a  cell  towards  salts  therefore  varies  with  each  individual  salt.  Solu- 
tions of  those  by  which  it  is  perfectly  permeable  have  the  same  ef- 
fects as  pure  water ;  but  the  less  diffusible  the  salt,  the  more  tendency 
it  has  to  prevent  the  entrance  of  the  water  in  which  it  is  dissolved,  and 
if  in  sufficient  concentration,  to  withdraw  fluid  from  the  cell.  A  per- 
fectly diffusible  substance  can  never  prevent  the  entrance  of  fluid, 
however  concentrated  be  its  solution. 

All  the  cells  of  the  body  do  not  resemble  each  other  in  their  per- 
meability, nor  in  the  salts  which  diffuse  into  them.  For  example,  the 
intestinal  epithelium  takes  up  some  of  the  salts  of  the  alkalies,  while 
the  red  blood  cells  do  not. 

An  even  more  obscure  relation  between  the  salts  and  colloids  has 
been  discovered  by  Hofmeister,  who  found  that  gelatin  plates  thrown 
into  weak  salt  solutions  absorb  more  fluid  than  when  they  are  put  in 
distilled  water,  and  who  inferred  from  this  that  colloid  substances 
have  a  special  affinity  for  salts  quite  apart  from  their  permeability  by 
water,  and  that  they  are  not  merely  passively  permeated  by  salt  solu- 
tions, but  have  an  active  attraction  for  some  of  the  salts  contained  in 
them.  This  affinity,  which  may  depend  on  the  same  factor  as  the 
permeability  of  the  cell,  varies  for  different  salts. 

The  role  played  by  the  physical  forces  in  the  salt-action  is  thus  determined 
not  only  by  the  physical  properties  of  the  fluids,  but  also  by  the  "affinity  " 
of  the  cell  contents  for  certain  of  the  constituents  of  these  fluids.  In  con- 
clusion it  may  be  stated  that  these  physical  forces  are  not  sufficient  to  explain 
the  whole  processes  of  absorption  and  excretion,  as  has  sometimes  been  stated ; 
the  physical  forces  merely  influence  the  processes  of  nutrition,  which  depend 
on  forces  hitherto  unexplained  and  possibly  exercised  only  by  the  living  proto- 
plasm. 

The  penetrating  power  of  salts  seems  to  be  connected  with  the  property 
which  many  of  the  a  possess  of  precipitating  certain  colloid  substances  from 
their  solutions  in  water,  for  those  salts  which  permeate  gelatin  plates  are 
found  to  precipitate  colloids  less  than  others.  Thus  the  sulphates  of  the  alka- 
lies, which  permeate  gelatin  plates  with  difficulty,  throw  globulins  out  of 
Solution  much  more  readily  than  the  chlorides.  Here  again,  however, 
different  colloids  vary  in  their  affinities,  some  reacting  to  one  sulphate  and 
not  to  another.  This  reaction  is  not  confined  to  the  proteids  but  extends  to 
many  carbohydrate  colloid  substances. 

In  the  dilute  solutions  found  in  the  tissues,  the  salts  do  not  exist  as 

1  An  isotonic  solution  is  here  used  to  indicate  a  solution  in  which  the  osmotic  pressure 
is  equal  to  that  of  the  blood  serum,  and  (presumably)  to  that  of  the  contents  of  the  red 
blood  cells. 


484  INORGANIC  SALTS,  ACIDS  AND  EASES. 

such,  but  are  largely  dissociated  into  two  or  more  Ions  charged  with 
positive  and  negative  electricity.  Thus  if  a  small  quantity  of  potassic 
chloride  be  dissolved  in  water,  it  is  dissociated  into  a  positive  K  ion 
(Ration)  and  a  negative  Cl  ion  (Anion).1  Similarly  sodium  sulphate 
dissolved  in  water  exists  as  two  Na  ions  and  a  negative  SO4  ion.  One 
effect  of  this  is  that  the  osmotic  pressure  of  such  a  dilute  solution 
diverges  considerably  from  what  might  be  expected  if  it  were  calcu- 
lated from  the  number  of  molecules  present,  because  each  of  the  ions 
exerts  the  same  osmotic  pressure  as  a  whole  molecule.  But  a  more  im- 
portant fact  is  that  the  ions  of  a  salt,  and  not  the  whole  molecule,  form 
chemical  combinations,  and  thus  exert  their  pharmacological  action. 
Thus  what  is  known  as  the  action  of  many  poisons  is  really  the  action 
not  of  the  molecule  as  a  whole,  but  of  one  of  the  ions.  For  example, 
cyanide  of  potassium  is  said  to  possess  a  very  poisonous  action,  but 
this  is  due  not  to  the  molecule  KCN  as  such,  but  to  the  CN  ion, 
which  forms  from  it  in  solution.  When  ferrocyanide  of  potassium  is 
dissolved,  on  the  other  hand,  no  CN  ion  is  formed,  the  salt  dissociat- 
ing into  the  K  and  Fe  (CN)^  ions,  and  ferrocyanide  of  potash  is  there- 
fore entirely  devoid  of  the  cyanide  action.  In  the  same  way  the 
corrosive  effects  of  potassium  or  sodium  hydrate  are  not  due  to  the 
potassium  or  sodium,  but  to  the  hydroxyl  ions  (HO),  for  the  same  K 
or  Na  ions  are  obtained  when  KC1  or  NaCl  is  dissolved,  but  neither 
of  these  is  corrosive.  Thus  when  a  dissociable  body  is  administered, 
not  one,  but  two,  separate  agents  are  put  in  action  in  the  tissues,  and 
in  describing  the  effects  of  one  of  these  dissociable  bodies,  the  effects 
of  each  ion  have  to  be  taken  into  consideration.  In  the  organic 
materia  medica,  many  such  substances  occur,  but  in  the  great  majority 
of  them  the  action  of  one  ion  is  so  much  more  powerful  than  that  of 
the  other  that  the  less  important  one  may  be  neglected.  Thus,  mor- 
phine sulphate  in  the  body  exists  as  a  morphine  and  a  sulphate  ion, 
but  the  action  of  morphine  is  so  much  the  more  powerful  that  the  sul- 
phate ion  may  be  left  out  of  account.  This  is  shown  by  the  fact  that 
morphine  hydrochlorate,  which  is  dissociated  into  morphine  and  chlo- 
ride ions,  has  practically  the  same  action  as  morphine  sulphate.  In 
the  same  way  the  positive  ion  (Na,  K,  etc.)  of  the  cyanides  may  be 
neglected,  because  the  negative  CN  ion  is  so  poisonous  that  the  posi- 
tive ion  can  never  be  present  in  the  tissues  in  sufficient  quantity  to 
elicit  any  action. 

When,  however,  less  poisonous  substances  are  involved,  the  case  is 
quite  different.  Thus,  although  the  hydrobromate  and  the  sulphate 
of  morphine  may  be  described  as  possessing  the  same  action,  because 
the  morphine  ion  alone  is  taken  into  account,  the  sulphate  and  brom- 
ide of  potassium  induce  quite  different  symptoms,2  because  here  larger 

1  These  ions  are  not  to  be  confused  with  atoms  of  potassium  and  chlorine  for  they 
possess  none  of  the  cheaiical  properties  of  these  elements  ;  the  physical  difference  con- 
sists in  each  ion  being  charged  with  a  burden  of  electricity,  positive  or  negative. 

2  Even  at  the  present  day  it  is  sometimes  a  matter  of  discussion  whether  the  bases  or 
the  acids  are  the  determining  factors  in  the  action  of  the  salts  of  the  alkalies.     The 
question  depends  entirely  upon  which  salts  are  compared.     If  chloride  of  sodium  and 


SALT-ACTION.  485 

quantities  can  be  administered,  and  the  SO4  and  Br  ions  are  present 
in  sufficient  quantities  to  elicit  their  specific  action,  which  is  quite  as 
important  as  that  of  the  K  ion. 

In  this  connection  it  is  to  be  noted  that  many  bodies  are  not  disso- 
ciated. For  example,  potash,  KHO,  and  alcohol,  C2H_HO,  both  con- 
tain HO,  but  in  the  former  the  hydroxyl  is  dissociated  in  water, 
while  the  latter  remains  undissociated.  Thus,  when  KHO  comes  in 
contact  with  a  mucous  membrane,  the  molecule  does  not  act  as  such, 
but  the  effects  are  due  to  the  HO  ion,  and  to  a  less  extent,  to  the  K 
ion.  On  the  other  hand,  alcohol  acts  as  a  molecule,  and  the  caustic 
effects  of  the  HO  ion  are  not  observed  under  it.  A  similar  contrast  is 
offered  by  the  effects  of  the  dissociable  KBr  and  bromated  camphor, 
which  is  not  dissociable  but  acts  as  an  entire  molecule.  It  is  therefore 
vain  to  expect  the  bromide  action  from  this  compound,  for  the  bromides 
act  from  the  presence  of  the  bromide  ion,  which  is  not  formed  from 
mouobromated  camphor. 

This  renders  the  classification  of  the  inorganic  salts  a  matter  of 
some  difficulty,  for  it  is  necessary  to  consider  the  action  of  each  ion 
alone,  and  then  to  find  how  far  its  effects  are  modified  by  the  presence 
of  the  other  ion  with  which  it  is  associated  in  the  molecule.  It  is 
obviously  illogical  to  consider  under  a  "  potassium  series"  all  the 
salts  of  potash,  for  in  many  of  these  the  K  ion  is  of  no  importance, 
while  in  others  it  is  the  chief  factor. 

The  effects  of  an  ion  cannot  be  determined  except  by  administering 
it  along  with  another  in  the  form  of  a  salt,  but  certain  ions  are  so  inac- 
tive in  the  tissues  that  if  any  effect  is  noted  after  a  compound  of 
which  they  form  part,  the  action  can  be  ascribed  with  certainty  to  the 
other  ion,  unless  the  change  arises  from  alteration  of  the  physical  prop- 
erties of  the  fluids.  For  example,  the  sodium  ion  (Na)  and  the  chloride 
ion  (Cl)  are  both  practically  inert,  except  in  so  far  as  they  change  the 
osmotic  pressure.  Thus,  if  a  sodium  salt  or  a  chloride  be  found  to 
cause  some  change  which  is  not  due  to  the  physical  alteration,  the  ac- 
tion is  attributed  to  the  other  ion  of  the  molecule.  Before  entering 
on  the  study  of  the  action  on  the  ions,  however,  it  is  obviously  neces- 
sary to  learn  the  symptoms  caused  by  alteration  of  the  physical  prop- 
erties of  the  fluids,  and  this  can  best  be  done  by  examining  the  effects 
of  bodies  which  act  only  in  this  way,  namely,  chloride  of  sodium  and 
water. 

BIBLIOGRAPHY. 

Naegeli.     Pflanzenphysiologische  Untersuchungen,  1855. 

De  Vries.     Pringsheim's  Jahrb.  f.  wissenschaft.  Botanik,  xiv.,  p.  427. 

Eykmann.     Pfliiger's  Arch.,  Ixviii.,  p.  58. 

Hedin.     Ibid.,  Ixx.,  p.  525. 

Koeppe.     Ibid.,  Ixvii.,  p.  189. 

Gryns.     Ibid.,  Ixiii.,  p.  86. 

chloride  of  potash  be  compared,  the  determining  factor  is  the  base,  but  if  a  chloride 
and  a  cyanide  be  in  question,  the  base  with  which  they  are  combined  is  practically  of 
no  importance. 


486  INORGANIC  SALTS,   ACIDS  AND  BASES. 

Hqfmeister.  Arch.  f.  exp.  Path.  u.  Pharm.,  xxiv.,  p.  247  ;  xxv.,  p.  1 ;  xxvii.,  p.  395 ; 
xxviii.,  p.  210. 

Hamburger.    Osmotische  Druck  und  lonenlehre,  1904. 

PaulL     Beitrage  z.  chem.  Phys.  u.  Path.,  ii.,  iii.,  v. 

Pohl.     Zts.  f.  physiol.  Chera.,  xiv.,  p.  151. 

For  the  adaptation  of  the  theory  of  ions  to  pharmacology,  consult : 

Scheurlen.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii.,  p.  74. 

Scheurlenu.  Spiro.    -Munch,  med.  Woch.,  1897,  p.  81. 

Loeb.     Pfliiger's  Arch.,  Ixix.,  p.  1. 

Schmiedebery.     Grundriss  der  Arzneimittellehre,  3d  ed.,  pp.  241-243. 

Kronig  u.  Paul.     Zts.  f.  Hyg.,  xxv.,  p.  1. 

I.     SODIUM   CHLORIDE   AND   WATER. 

The  most  typical  example  of  salt-action  is  presented  by  chloride  of 
sodium,  for  this  salt  is  always  present  in  large  quantities  in  the  body, 
and  has  practically  no  specific  action  ;  the  sodium  and  chloride  ions 
are  ordinary  and  necessary  constituents  of  the  fluids  of  the  body.  The 
action  of  this  salt  is  therefore  limited  to  the  alteration  in  the  physical 
properties  of  the  fluids,  which  its  presence  in  excess  or  in  limited 
amount  induces.  In  the  same  way  the  action  of  water  is  due  only  to 
its  diluting  the  body  fluids  and  lessening  their  osmotic  pressure,  and 
it  may  therefore  be  described  along  with  that  of  salt. 

Most  of  the  tissues  hitherto  examined  in  regard  to  this  point  have 
proved  permeable  by  both  the  Na  and  the  Cl  ions,  but  in  every  case 
there  is  a  certain  amount  of  resistance  oifered  so  that  the  presence  of 
salt  in  the  fluid  round  a  cell  always  prevents  its  free  diffusion  into  the 
interior ;  i.  e.,  sodium  chloride  solution  exerts  osmotic  pressure  on  the 
cell.  The  molecular  weight  of  common  salt  being  small,  the  osmotic 
changes  induced  by  it  are  greater  than  those  induced  by  an  equal 
weight  of  most  other  salts,  because  a  larger  number  of  molecules  ex- 
ist in  each  gramme.  It  also  dissociates  into  its  two  ions  more  readily 
than  many  others,  and  this  lends  it  still  greater  osmotic  power. 

A  common  example  of  the  osmotic  action  of  salt  is  seen  in  its  use 
to  preserve  meats  from  putrefaction,  which  it  accomplishes  by  with- 
drawing the  fluids  of  the  meat,  and  thus  rendering  it  dry  and  hard 
and  unsuitable  for  the  growth  of  microbes. 

In  the  same  way  the  Red  Blood  Corpuscles  shrink  in  size  when  they 
are  placed  in  a  solution  of  salt  which  is  stronger  than  the  blood-plasma 
(hypertouic),  because  the  water  is  withdrawn  from  them.  In  dilute 
(hypotonic)  solution,  on  the  other  hand,  or  in  water,  they  swell  up  be- 
cause they  absorb  water,  while  in  solutions  of  the  same  osmotic  pres- 
sure as  the  plasma  (iso tonic)  they  remain  unaltered  in  size.  When 
water  is  absorbed  into  the  corpuscles  some  obscure  change  takes  place 
in  them,  and  the  hemoglobin  diffuses  into  the  surrounding  liquid. 

Muscle  is  affected  in  a  similar  way,  strong  salt  solutions  withdrawing 
fluid  from  it,  while  weaker  ones  are  absorbed,  and  both  tend  to  destroy 
its  vitality  in  a  longer  or  shorter  time.  In  isotonic  salt  solution,  on 
the  other  hand,  muscle  preserves  its  irritability  for  many  hours. 
Strong  salt  solutions  irritate  exposed  Nerves  from  the  withdrawal  of 
their  fluid  contents,  and  on  the  other  hand,  distilled  water  is  equally 
fatal  to  them. 


SODIUM  CHLORIDE  AND   WATER.  487 

These  changes  are  undoubtedly  due  to  the  imperfect  permeability  of  the 
cells  by  the  sodium  and  chloride  ions,  and  as  regards  the  red  blood  cor- 
puscles, it  is  definitely  known  that  salt  penetrates  them  with  the  greatest 
difficulty,if  at  all,  and  the  changes  induced  in  them  by  solutions  of  different 
concentration  and  by  water  are  due  to  the  alteration  of  their  fluid  contents 
only.  If  this  were  true  for  all  cells,  the  isotonic  solution  would  preserve 
them  in  a  normal  condition  until  they  slowly  perished  for  want  of  oxygen 
and  from  exhaustion  of  their  reserve  of  food.  But  this  is  found  not  to  be 
the  case,  for  muscle  suspended  in  isotonic  solution  often  develops  a  more  or 
less  rhythmical  series  of  contractions,  while  the  frog's  heart  ceases  to  beat 
after  a  time  when  it  is  perfused  with  isotonic  salt  solution,  although  it  has 
not  exhausted  its  energy  entirely.  Similarly  some  ova  and  fish  living  in  sea 
water  die  if  they  are  put  in  a  solution  of  sodium  chloride  isotonic  with  sea 
water  while  they  live  much  longer  in  distilled  water.  It  is  obvious  that  in 
these  instances  no  changs  in  the  distribution  of  the  fluids  can  occur,  for  the 
osmotic  pressure  of  the  fluid  is  unchanged.  In  other  words  the  death  of 
these  animals  in  pure  salt  solution  is  due  not  to  the  physical  action  of  the 
salt  (salt  action),  but  to .  the  sodium  ion  exercising  a  deleterious  effect  on 
them.  This  deleterious  action  may  be  neutralized  by  the  addition  of  traces 
of  salts  of  calcium  or  of  some  other  bivalent  elements,  while  the  monovalent 
kations  have  less  antagonistic  effects  (Loeb).  In  the  natural  environment  of 
living  cells  both  sodium  and  calcium  are  present,  so  that  the  toxic  effect  of 
sodium  (see  Calcium)  can  scarcely  be  observed  except  when  small  masses 
of  tissue  are  thoroughly  washed  with  salt  solution  ;  as  far  as  the  higher  animals 
are  concerned,  then,  salt  may  be  regarded  as  indifferent  in  itself  and  as  acting 
only  through  changing  the  distribution  of  the  fluids.  And  as  isotonic  solutions 
have  no  osmotic  action,  they  are  entirely  inert. 

Water  or  very  dilate  salt  solutions  penetrate  into  the  superficial  cells 
of  the  Skin,  which  therefore  become  swollen  and  softened.  Concen- 
trated solutions  on  the  other  hand  rather  tend  to  draw  fluid  from  the 
surface  cells,  and  this  along  with  the  passage  of  salt  into  them,  causes 
some  mild  irritation.  Neither  salt  nor  water  is  absorbed  into  the  cir- 
culation through  the  skin  in  mammals.  A  much  greater  absorption 
into  the  superficial  tissues  occurs  on  less  protected  parts,  such  as  the 
cornea,  which  becomes  white  and  clouded  when  strong  salt  solutions 
are  applied  to  it.  Similarly,  either  pure  water  or  strong  salt  solution 
causes  considerable  pain  and  smarting  in  the  nasal  passages,  or  in 
wounds,  from  the  disturbance  of  the  normal  relation  of  salt  and  fluid 
in  the  surface  cells.  Isotonic  solutions  on  the  other  hand  cause  no 
pain. 

In  the  Mouth  salt  has  a  characteristic  taste,  and  strong  solutions  act 
as  astringents  here  and  in  the  throat.  In  the  Stomach  its  action  is 
very  much  like  that  on  other  mucous  membranes,  hypotonic  solutions 
causing  swelling,  while  hypertonic  solutions  cause  a  withdrawal  of  fluid 
and  a  shrinking  of  the  cells.  This  withdrawal  of  fluid  and  imbibition 
of  salt  may  set  up  such  irritation  as  to  induce  vomiting. 

The  digestion  in  the  stomach  does  not  always  seem  to  be  improved 
by  salt  in  the  food,  for  even  small  quantities  have  been  found  to  lessen 
the  acidity  of  the  gastric  juice,  and  the  amount  of  albuminous  food  ab- 
sorbed from  the  alimentary  canal  in  animals  is  but  little  altered  when 
salt  is  added  to  the  food.  It  is  very  possible,  however,  that  a  small 
quantity  of  salt  in  the  food  renders  it  more  palatable  in  many  instances, 


488  INORGANIC  SALTS,  ACIDS  AND  BASES. 

and  thus  increases  the  reflex  flow  of  the  gastric  juice.  (Compare  Bitters, 
page  56.)  Dapper  finds  that  the  hydrochloric  acid  of  the  stomach  is 
increased  in  some  persons,  and  diminished  in  others  by  mineral  waters 
containing  common  salt  as  their  chief  ingredient.  This  is  only  to  be 
explained  by  supposing  that  these  waters  have  no  effect  on  the  secre- 
tion directly,  but  alter  it  by  changing  the  nutrition  of  the  gastric 
mucous  membrane. 

Salt  solutions  are  Absorbed  both  in  the  stomach  and  bowel,  but  con- 
siderable difference  of  opinion  exists  as  to  the  means  by  which  this  is 
accomplished.  An  attempt  has  been  made  to  explain  absorption  by 
the  action  of  the  known  physical  processes,  such  as  diffusion,  osmosis 
and  filtration,  but  these  seem  quite  inadequate  without  the  assumption 
that  there  is  a  constant  tendency  for  fluids  and  for  some  salts  to  pass 
inwards  from  the  lumen  of  the  bowel  and  stomach.  This  tendency 
may  be  opposed  or  strengthened  by  the  osmotic  pressure.  Thus  hypo- 
tonic  solutions  and  water  are  absorbed  rapidly,  because  here  not  only 
is  the  natural  flow  inwards,  but  the  osmotic  current  is  in  the  same 
direction,  the  fluid  being  of  lower  osmotic  pressure  than  the  blood 
serum ;  but  even  pure  water  appears  not  to  be  absorbed  from  the 
stomach  until  it  has  acquired  a  certain  content  of  salts  which  diffuse 
into  it  from  the  blood.  In  solutions  of  equal  osmotic  pressure  with 
the  blood  serum  the  absorption  is  slower,  because  here  the  natural  flow 
alone  is  active,  while  hypertonic  solutions  are  still  more  slowly  absorbed 
or  may  even  be  increased  at  first,  because  the  osmotic  pressure  acts  in 
the  opposite  direction  from  the  natural  flow.  Accordingly,  while  hypo- 
tonic  and  isotonic  solutions  disappear  rapidly,  the  absorption  of  the 
stronger  solutions  may  be  preceded  by  a  period  in  which  the  fluid  of 
the  bowel  actually  increases,  water  diffusing  into  it  from  the  blood. 
At  the  same  time  the  salt  is  being  absorbed,  and  the  solution  eventually 
becomes  isotonic,  and  is  absorbed.  The  absorption  from  the  bowel  is 
very  similar  to  that  described  by  Hofmeister  in  gelatine  plates,  and  it 
is  possible  that  the  unexplained  tendency  for  fluids  to  pass  inwards 
may  be  due  to  some  "  affinity  "  between  the  salts  and  the  colloids  of 
the  bowel  wall. 

The  Blood  and  Lymph  are  in  turn  affected  by  these  processes.  When 
hypotonic  solutions  pass  into  the  blood  from  the  bowel,  the  proportion 
of  solids  and  liquid  is  of  course  changed,  and  fewer  corpuscles  and  less 
solid  matter  are  found  in  the  cubic  millimetre  than  normally  (hydrse- 
mia).  On  the  other  hand,  when  strong  salt  solutions  in  the  bowel 
cause  the  effusion  of  fluid,  the  blood  becomes  more  concentrated  than 
in  ordinary  conditions.  After  the  reabsorption  of  the  fluid,  the  normal 
balance  of  plasma  and  corpuscles  must  be  restored,  and  to  effect  this 
currents  are  set  up  between  the  blood  and  the  fluid  of  the  surrounding 
lymph.  These  currents  have  been  investigated  by  the  injection  of  salt 
solutions  directly  into  the  blood,  and  not  by  their  absorption  from  the 
bowel,  but  the  processes  probably  resemble  each  other  in  their  chief 
features.  When  the  blood  is  rendered  hypertonic  by  the  injection 
of  strong  salt  solution,  the  lymph  at  once  begins  to  pour  into  the  blood 


SODIUM  CHLORIDE  AND  WATER.  489 

vessels  by  osmotic  attraction,  and  this  leads  to  hydraBmia  and  increased 
capillary  pressure,  the  arterial  tension  remaining  unchanged.  This 
augmentation  of  the  capillary  pressure  in  turn  induces  a  flow  of  lymph 
from  the  blood  vessels  into  the  lymph  spaces. 

The  flow  of  lymph  from  the  blood  vessels  is  first,  therefore,  dimin- 
ished in  amount  by  the  presence  of  salt  in  the  intestine  and  blood,  and 
then  increased  again  by  the  high  capillary  pressure.  This  interchange 
between  the  blood  and  lymph  is  continued,  because  as  the  salt  is  ex- 
creted by  the  kidneys  and  other  excretory  glands,  a  continual  varia- 
tion in  the  osmotic  pressure  of  both  blood  and  lymph  occurs. 

The  details  of  the  changes  between  the  blood  and  lymph  under  the 
action  of  salt  and  water  are  still  obscure,  but  there  is  no  question  that 
the  absorption  of  either  of  these  leads  to  an  augmentation  of  the  normal 
exchange  of  these  fluids.  In  particular,  it  is  still  undecided  whether 
the  cells  of  the  vessels  possess  a  secretory  function  similar  to  that  of 
the  secretory  glands,  or  whether  the  whole  process  may  be  attributed 
to  variations  of  osmotic  pressure  and  filtration. 

The  changes  in  the  blood  and  lymph  are  followed  by  an  increased 
activity  of  the  Excretory  Organs.  Thus  the  urine l  is  much  augmented 
by  the  injection  of  salt  solution  into  the  blood,  less  so  by  the  absorption 
of  water  or  salt  solution  from  the  stomach  and  bowel.  A  good  deal  of 
discussion  has  been  carried  on  in  recent  years  as  to  the  cause  of  the 
diuresis  from  salts  and  water,  and  some  authorities  hold  that  the 
presence  of  salt  in  excess  in  the  blood  stimulates  the  renal  cells  much 
in  the  same  way  as  caffeine.  But  a  more  plausible  explanation  is  that 
the  greater  volume  of  the  blood,  following  the  absorption  of  the 
fluid  and  the  increased  flow  of  lymph,  results  in  an  increase  in  the 
capillary  pressure  in  the  glomerulus  and  this  in  turn  promotes  the 
escape  of  fluid  into  the  capsule.  A  more  rapid  flow  through  the 
tubules  follows,  and  the  glomerular  secretion  lies  in  them  for  a  shorter 
time,  so  that  there  is  less  tendency  for  its  constituents  to  be  reabsorbed 
into  the  blood  vessels ;  the  fluid  reaching  the  ureters  is  accordingly 
increased  and  the  dissolved  salts  and  urea  are  also  augmented ;  those 
constituents  which  in  ordinary  circumstances  are  absorbed  most  readily 
by  the  epithelium  of  the  tubules  are  increased  more  than  the  others,  so 
that  the  chlorides,  and  the  potassium  and  sodium  of  the  urine  rise 
much  more  than  the  urea,  phosphates  or  sulphates  even  when  the 
diuresis  is  due  to  the  absorption  of  water.  Any  other  diffusible  body 
increases  the  urine  in  the  same  way  as  salt,  and  urea  has  therefore  been 
suggested  as  a  diuretic  ;  it  differs  from  salt  in  the  difficulty  with  which 
it  is  absorbed  from  the  tubules  of  the  kidney  and  this  further  retards 
the  absorption  of  the  fluid,  so  that  urea  may  probably  have  a  more 
powerful  diuretic  action  than  sodium  chloride. 

Other  secretions,  such  as  the  saliva,  are  increased  by  salt,  and  this 

f  l  The  following  explanation  of  the  diuresis  is  based  upon  the  theory  that  all  the  con- 
stituents of  the  urine  are  excreted  by  the  glomerulus,  and  that  some  of  them,  notably 
much  ot  the  fluid  and  the  alkali  chlorides,  are  reabsorbed  in  passing  through  the 
tubules.  See  Journ.  of  Physiol.,  xxvii. ,  p.  429;  xxviii.,  p.  ,431 


490  INORGANIC  SALTS,   ACIDS  AND  BASES. 

not  only  by  a  reflex  from  the  mouth,  but  also  because  some  of  the  salt 
is  excreted  by  the  salivary  glands. 

When  very  large  amounts  of  isotonic  salt  solution  are  thrown  into 
the  blood,  the  organism  may  have  difficulty  in  excreting  it  rapidly 
enough,  and  the  tissues  are  therefore  found  to  be  swollen  and  redema- 
tous  in  some  parts  of  the  body. 

When  salt  solution  is  injected  into  the  serous  cavities  or  into  the 
lymph  spaces,  absorption  occurs  in  the  same  way  as  from  the  alimentary 
canal,  except  that  in  the  case  of  the  serous  cavities  osmosis  seems  to 
play  a  greater,  and  the  other  forces  a  smaller  role,  than  in  the  stomach 
and  intestine. 

The  administration  of  large  quantities  of  fluid,  either  as  water  or 
as  dilute  salt  solution,  might  be  expected  to  have  some  effect  on  the 
general  Tissue  Change,  through  the  increased  movement  of  the  lymph 
flushing  out  the  cells  and  leading  to  a  more  complete  removal  of  the 
waste  products.  As  a  matter  of  fact,  some  increase  in  the  nitrogen 
and  sulphur  eliminated  in  the  urine  has  been  observed  under  the  use 
of  large  quantities  of  water,  but  it  is  impossible  to  estimate  at  present 
how  far  this  may  be  due  to  the  diuresis  alone  ;  in  any  case  the  increase 
is  not  by  any  means  so  large  as  is  often  believed,  as  it  only  amounts  to 
some  5  per  cent.,  or  less.  Any  salt  solution  causing  an  acceleration  in 
the  movement  of  the  fluids  of  the  body  must  tend  to  facilitate  the 
excretion  of  the  waste  products  in  the  same  way,  but  some  recent 
investigations  indicate  that  in  addition  salt  tends  to  lessen  the  proteid 
metabolism  through  acting  directly  on  the  cells  ;  this  action  is  so  slight, 
however,  that  the  resulting  fall  in  the  nitrogen  eliminated  is  concealed 
by  the  increase  caused  by  the  more  complete  flushing  and  diuresis. 
The  amount  of  proteids  and  fats  absorbed  from  the  alimentary  tract 
does  not  appear  to  be  altered  by  the  administration  of  large  amounts 
of  water  (Edsall). 

Strong  salt  solutions  injected  into  animals  either  hypodermically  or  intra- 
venously sometimes  prove  fatal,  apparently  from  the  withdrawal  of  fluid 
from  the  central  nervous  system.  The  symptoms  in  mammals  are  increas- 
ing lassitude  and  weakness,  with  augmented  reflex  excitability,  tremors,  and 
finally  convulsions.  The  circulation  is  only  slightly  affected  until  just  before 
death,  when  the  blood-pressure  falls  suddenly.  The  red  blood  cells  are 
found  to  be  much  shrunken,  and  according  to  Heinz,  form  thrombi  in  many 
vessels.  Haemorrhages  are  found  in  different  organs,  the  lungs  are  oadema- 
tous,  and  the  intestinal  mucous  membrane  is  swollen  and  congested. 

The  Salts  of  the  Urine  are  increased  by  diuresis  from  any  cause  as 
has  been  stated  ;  both  sodium  and  potassium  are  augmented  but  espe- 
cially the  sodium  which  is  present  in  larger  proportions  in  the  serum 
and  therefore  forms  a  larger  constituent  of  the  glomerular  secretion. 
This  increase  in  the  sodium  salts  is  of  course  particularly  marked  when 
diuresis  is  induced  by  common  salt,  but  when  potassium  salts  increase 
the  urine,  the  sodium  also  generally  predominates  in  it  and  this  would 
eventually  lead  to  the  loss  of  all  the  sodium  in  the  blood  of  herbivora, 
whose  food  contains  large  quantities  of  potassium ;  but  after  a  certain 


SODIUM  CHLORIDE  AND    WATER.  491 

amount  of  sodium  has  been  lost,  potassium  causes  no  further  excretion 
so  that  the  tissues  apparently  protect  themselves  from  the  total  loss  of 
sodium  chloride,  which  would  be  fatal  to  them. 

Bunge  states  that  in  both  man  and  animals  a  diet  lich  in  potassium  causes 
an  appetite  for  common  salt,  while  a  diet  which  does  not  contain  an  excess 
of  potash,  does  not  develop  this  desire.  Thus  herbivorous  animals  and 
agricultural  peoples  seek  for  salt,  because  vegetable  foods  contain  large 
quantities  of  potassium,  while  the  carnivora  and  the  hunting  peoples  require 
no  salt  and  often  have  a  distaste  foi  it,  owing  to  their  food  containing  a  larger 
relative  proportion  of  sodium  salts.  This  instinctive  appetite  he  regards  as 
a  means  by  which  nature  protects  the  tissues  from  excessive  loss  of  sodium. 
Some  doubt  has  recently  been  thrown  on  this  explanation  of  the  desire  for 
salt  by  Lapicque,  who  discovered  some  African  races  living  on  vegetable  sub- 
stances alone,  and  using  the  ashes  of  the  plants,  which  contain  more  potas- 
sium than  sodium,  as  civilized  peoples  use  ordinary  salt.  He  holds,  there- 
fore, that  salt  is  merely  of  value  as  a  flavoring  agent. 

Therapeutic  Uses.  —  Water  and  salt  are  rarely  or  never  prescribed  as 
such,  but  are  used  to  a  very  large  extent  in  medicine,  and  great  virtues 
have  been  ascribed  to  them  in  a  number  of  pathological  conditions. 

They  are  used  for  their  local  action,  and  for  the  supposed  alterations 
in  the  tissue-change  and  in  the  excretions  produced  by  them  after  their 
absorption  into  the  blood.  In  general,  patients  are  sent  to  watering 
places  and  baths,  and  the  success  of  the  treatment  is  to  a  considerable 
extent  due  to  the  climatic  conditions,  the  change  in  the  habits  of  life, 
the  dietetic  treatment,  and  the  rest  from  everyday  occupations.  At 
the  same  time  the  drinking  of  large  quantities  of  weak  salt  solutions, 
and  the  constant  bathing  in  somewhat  irritating  fluids,  may  exercise  a 
therapeutic  action  in  many  cases,  and  may  at  any  rate  aid  the  hygienic 
conditions.  Whether  the  water  contains  salt  or  not,  it  must  be  remem- 
bered that  in  bathing  the  action  is  a  purely  local  one,  for  neither  the 
salt  nor  the  water  is  absorbed.  The  slightly  irritant  effect  on  the  skin 
may,  however,  improve  its  circulation  and  nutrition,  and  thereby  be 
efficacious  in  some  skin  diseases.  By  continued  use,  the  sensitiveness 
of  the  skin  vessels  to  heat  and  cold  may  also  possibly  be  deadened. 
Remarkable  effects  on  the  tissue  change  have  been  alleged  to  be  pro- 
duced by  bathing  in  strong  salt  solutions,  owing  to  their  counter- 
irritant  action.  For  example,  the  excretion  of  urea  and  the  oxidation 
in  the  body  are  often  said  to  be  much  increased,  but  these  results  have 
not  been  confirmed  after  further  experience.  Special  baths  are  very 
frequently  recommended  for  some  diseases,  but  it  must  be  remembered 
that  the  action  is  due  to  the  salt-action  ;  the  greater  the  concentration, 
the  greater  is  the  effect  on  the  skin,  and  it  is  of  no  importance  which 
of  the  neutral  salts  is  in  the  solution,  or  whether  small  traces  of  iron 
or  other  metals  are  present ;  alkaline  baths  are  more  stimulant  than 
others. 

In  diseases  of  the  stomach  the  drinking  of  large  quantities  of  water 
or  of  weak  salt  solutions  may  also  be  beneficial.  The  action  is  similar 
to  that  on  the  skin — a  mild  irritation,  owing  to  the  swelling  up  of 


492  INORGANIC  SALTS,  ACIDS  AND  BASES. 

the  more  superficial  cells  of  the  epithelium  and  the  increased  move- 
ment of  the  fluid  in  them  and  in  the  deeper  layers.  In  some  cases  of 
insomnia  hot  water  sometimes  causes  sleep,  probably  by  causing  dila- 
tation of  the  gastric  vessels,  and  thereby  withdrawing  the  blood  from 
the  brain. 

In  many  diseases  in  which  the  symptoms  point  to  a  disorder  of  the 
metabolism,  water  and  salt  solutions  are  advised.  Thus  gout  and 
rheumatism  are  frequently  treated  by  sending  the  patients  to  watering 
places,  on  the  theory  that  the  tissues  are  washed  out  thoroughly,  and 
the  waste  products  thus  removed.  As  a  matter  of  fact,  the  more  recent 
work  in  this  direction  shows  that  large  quantities  of  water  and  dilute 
salt  solutions  have  little  or  no  effect  on  the  uric  acid  excretion,  which 
was  formerly  believed  to  be  much  diminished.  This  fact  does  not 
necessarily  involve  the  inference  that  the  treatment  is  erroneous,  for  it 
is  now  generally  recognized  that  gout  is  not  really  due  to  the  failure 
of  the  uric  acid  excretion.  Many  cases  are  unquestionably  benefited 
by  the  springs,  although  it  may  be  questioned  how  much  of  the 
improvement  is  due  to  the  water  taken,  and  how  much  of  it  ought  to 
be  ascribed  to  the  changed  conditions  of  life. 

The  bath  treatment  has  been  recommended  for  numerous  diseases 
in  which  the  salt  and  water  could  not  possibly  have  any  beneficial 
action,  and  in  which  the  remedial  agent  is  the  climate,  and  perhaps  the 
faith  of  the  patient  in  the  water.  Belief  in  the  healing  power  of  cer- 
tain natural  waters  is  one  of  the  most  ancient  of  all  therapeutic 
theories,  is  found  among  altogether  uncivilized  peoples,  and  has  been 
incorporated  in  many  religions.  It  is  not  to  be  wondered  at  that  in 
some  nervous  disorders  the  faith  of  the  patient  and  auto-suggestion 
perform  some  marvelous  "  cures." 

In  obesity  the  drinking  of  some  waters,  such  as  that  of  Kissingen 
or  Homburg,  has  been  advised.  These  waters  contain  from  0.2—1.4 
per  cent,  sodium  chloride,  and  it  seems  very  doubtful  if  they  have  any 
effects  in  themselves  ;  many  hold  that  the  benefits  accruing  from  the 
treatment  are  really  due  to  the  hygienic  measures  followed,  and  that 
the  waters  play  only  an  insignificant  role. 

Salt  in  solid  form  or  in  strong  solution  is  used  occasionally  as  an 
emetic  in  cases  of  emergency,  as  in  poisoning,  and  generally  produces 
vomiting  rapidly,  owing  to  the  irritant  action  on  the  stomach.  In 
nitrate  of  silver  poisoning  it  arrests  the  corrosive  action  by  the  forma- 
tion of  the  insoluble  silver  chloride. 

Salt  solution  is  often  used  instead  of  water  in  enemata,  and  when  con- 
centrated possesses  an  irritant  action  on  the  bowel,  producing  peri- 
stalsis. Strong  solutions  are  sometimes  thrown  into  the  rectum  to 
destroy  round  worms. 

Isotonic  salt  solutions  (0.6-0.9  per  cent.)  are  often  administered 
when  the  body  has  lost  much  fluid,  as  they  are  rapidly  absorbed  and 
are  devoid  of  irritant  action ;  thus  in  haemorrhage  these  solutions 
are  injected  subcutaneously,  intravenously,  or  per  rectum.  A  rapid 


SODIUM  CHLORIDE  AND    WATER.  493 

improvement  in  the  circulation  follows,  and  this  has  given  rise  to  the 
erroneous  opinion  that  such  saline  infusions  stimulate  the  heart  directly 
as  well  as  by  the  mechanical  effect  of  the  increase  in  the  fluids  of  the 
body ;  this  theory  has  led  to  infusions  being  made  in  weakness  of 
the  heart  from  other  causes  than  hemorrhage.  Some  of  the  symp- 
toms of  cholera  are  believed  to  be  due  to  the  loss  of  fluid,  and  these 
are  said  to  be  relieved  by  the  injection  of  salt  solutions,  though  the 
mortality  does  not  seem  materially  altered.  The  intravenous  and  sub- 
cutanous  injection  of  salt  solution  has  been  recommended  in  uremia 
and  similar  intoxications,  with  the  idea  of  washing  out  the  poisons 
through  the  kidneys  ;  the  same  results  can  often  be  obtained  by  drink- 
ing large  quantities  of  water.  There  is  still  some  question  as  to  whether 
the  infusion  of  salt  solution  is  really  remedial  in  loss  of  blood,  and  the 
latest  investigator  of  the  matter,  Feis,  comes  to  the  conclusion  that  it 
is  of  little  or  no  benefit.  The  hypodermic  injection  of  large  quantities 
of  isotonic  salt  solution  is" said  by  Bieruacki  to  have  effects  which  only 
pass  off  in  some  6—8  days  in  animals.  The  blood  was  at  first  much 
diluted,  but  afterwards  became  very  concentrated  and  after  a  few  days 
a  considerable  number  of  the  red  cells  were  found  in  a  state  of  disin- 
tegration, and  the  haemoglobin  thus  liberated  was  distributed  through 
the  plasma  until  it  was  finally  excreted  in  the  urine.  The  animals 
did  not  seem  to  suffer  from  the  treatment,  but  his  results  indicate  that 
the  injection  of  large  quantities  of  salt  solutions  is  by  no  means  the 
harmless  proceeding  which  it  is  generally  believed  to  be. 

Isotonic  salt  solutions  are  used  in  surgery  to  wash  out  the  peritoneal 
cavity,  which  would  be  injured  by  distilled  water. 

PREPARATIONS. 

Sodii  Chloridum  (U.  S.  P.,  B.  P.),  common  salt. 

Aqua  (U.  S.  P.). 

Aqua  Destillata  (U.  S.  P.,  B.  P.). 

BIBLIOGRAPHY. 

See  Salt-Action  (page  489)  and  Saline  Cathartics. 

Heidenhain.     Pfliiger's  Arch.,  xlix.,  p.  209;  Ivi.,  p.  579. 

Starling,  etc.     Journ.  of  Physiol.,  xvi.,  xvii.,  xviii.,  xix. 

Cohnstein.     Pfliiger's  Arch.,  lix.,  Ixii.,  Ixiii.     Virchow's  Arch.,  cxxxv.,  p.  514. 

Mendel.     Journ.  of  Physiol.,  xix.,  p.  227. 

Orlow.     Pfliiger's  Arch"!,  lix.,  p.  170. 

v.  Limbeck.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxv.,  p.  69. 

Dreser.     Ibid.,  xxix.,  p.  303. 

Reichmann.     Ibid.,  xxiv.,  p.  78. 

Munzer.     Ibid.,  xli.,  p.  74. 

Loeb.  Amer.  Journ.  of  Physiol.,  iii.,  pp.  327,  383,  434.  Pfl tiger's  Arch.,  Ixxxviii., 
p.  68 ;  xcvii.,  p.  394. 

Gabriel.     Ztschr.  f.  Biol.,  xi.,  p.  554. 

Heinz.     Virchow's  Arch.,  cxxii.,  p.  100. 

Bunge.  Lehrbuch  der  phys.  u.  path.  Chemie,  2d  ed.,  p.  107.  Ztschr.  f.  Biologie, 
xli.,  p.  484. 

Grawitz.     Zts.  f.  klin.  Med.,  xxii.,  p.  417. 

Ludwicj.     Centralbl.  f.  inn.  Med.,  1896,  Nos.  45  and  46. 

Weber.     Ergeb.  d.  Phys.,  iii.,  1,  p.  268  (metabolism). 

Loeb,  Mathews,  Zoethout,  Lillie,  etc.  Amer.  Joum.  of  Physiol.,  iii.-xi.  (antagonistic 
action  of  salts). 


494  INORGANIC  SALTS,  ACIDS  AND  BASES. 

Feis.     Virchow's  Arch.,  cxxxviii.,  p.  75. 

Biemac/ci.     Ztschr.  f.  klin.  Med.,  xix.,  Suppl.,  p.  49. 

Straub.     Ztschr.  f.  Biologie,  xxxvii.,  p.  527  ;  xxxviii.,  p.  537. 

Magnus  u.  Gottlieb.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv.  and  xlv. 

Lenhartz.     Deutsch.  Arch.  f.  klin.  Med.,  Ixiv.,  p.  189. 

Leon/acker.     Mittheil.  a.  d.  Grenzgebiete,  vi.,  p.  321. 

Taylor,  Frazier,  Edscdl.   Pepper  Laboratory  Keports,  Philadelphia,  1900,  pp.  356,  368. 

Soilmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi.,  p.  1. 

II.    POTASSIUM   SALTS. 

The  effects  of  potassium  in  the  organism  can  best  be  studied  by  ad- 
ministering the  chloride,  as  the  Cl  ion  is  practically  devoid  of  action 
and  the  symptoms  induced  by  potassic  chloride  must  therefore  be  due 
either  to  the  "  salt-action  "  or  to  the  potassium.  The  salt-action  can 
be  discounted  by  comparing  the  symptoms  with  those  of  an  isotonic 
solution  of  sodium  chloride,  and  when  this  is  done  it  is  found  that 
potassium  has  a  distinctly  poisonous  action,  which  is  chiefly  manifested 
in  depression  of  the  central  nervous  system  and  of  the  heart. 

In  the  frog  the  central  action  is  shown  by  the  spontaneous  move- 
ments becoming  weak  and  slowly  performed,  and  by  their  completely 
disappearing  much  earlier  than  in  sodium  chloride  experiments.  In 
mammals  the  chief  nervous  symptoms  are  great  muscular -weakness  and 
apathy.  The  respiration  becomes  rapid  and  labored,  probably  from 
the  anaemia  of  the  centres,  and  death  is  often  preceded  by  weak  as- 
phyxial  convulsions. 

The  depression  of  the  heart  is  shown  in  the  frog  by  weakness,  slow- 
ness and  irregularity  when  chloride  of  potassium  is  injected  subcu- 
taneously,  but  is  more  clearly  demonstrated  by  the  rapid  failure  of  an 
excised  heart  when  a  chloride  of  potassium  solution  is  perfused  through 
it.  An  isotonic  solution  of  common  salt  also  brings  the  heart  to  stand- 
still after  a  time,  but  potassic  chloride  acts  very  much  more  quickly, 
and,  in  fact,  the  former  may  restore  the  heart  beat  after  it  has  been 
stopped  by  potassium,  which  proves  conclusively  that  the  latter  has  a 
specific  poisonous  action  in  addition  to  any  salt-action.  Ringer,  how- 
ever, found  that  the  beat  of  the  frog's  heart  perfused  with  a  solution 
of  common  salt  was  not  so  satisfactory  as  that  of  one  perfused  with 
the  same  solution  to  which  some  potassic  salt  had  been  added,  because, 
as  has  been  already  mentioned,  the  proteids  of  the  heart  must  contain 
potassium,  and  when  this  is  substituted  by  sodium,  as  is  the  case  when 
there  is  no  potassium  in  the  perfusion  fluid,  the  muscle  becomes  in- 
capable of  normal  contraction.  (See  Calcium.) 

The  mammalian  heart  is  also  injured  by  the  action  of  potassium 
when  the  salt  is  administered  in  large  quantities,  as  is  shown  by  the 
pulse  becoming  much  slower  and  weaker  and  by  a  sudden  fall  of  blood- 
pressure  ;  an  acceleration  of  the  pulse  is  often  observed  at  first.  The 
poisonous  action  of  potash  on  the  heart  has  given  rise  to  exaggerated 
apprehensions  of  the  danger  of  using  its  salts  in  therapeutics,  and  it 
may  therefore  be  noted  that  potassium  has  practically  no  effect  on  the 
heart  when  given  by  the  stomach,  and  that  very  much  larger  quantities 
of  potash  are  taken  daily  in  the  food  by  thousands  of  persons  than  are 


POTASSIUM  SALTS.  495 

ever  prescribed  in  medicine.  Bunge  estimates  the  amount  of  potash  in 
the  food  of  some  classes  at  50-100  grms.  (1J-3  oz.)  per  day.  The 
absence  of  effects  from  the  potassium  ion  when  the  salts  are  taken  by 
the  mouth  is  due  to  their  rapid  excretion  in  the  urine. 

The  failure  of  the  heart  is  the  cause  of  death  in  mammals  when 
potassium  salts  are  injected  into  a  vein,  the  respiration  and  the  reflexes 
often  persisting  for  a  few  seconds  afterward.  According  to  Braun, 
potassium  salts  cause  a  transient  contraction  of  the  vessel  walls  when 
they  are  injected  directly  into  the  arteries. 

Potassium  has  some  action  on  muscle  in  the  frog,  the  contraction  seeming 
to  be  somewhat  greater  in  height,  though  shorter  in  length,  and  there  being 
less  tendency  to  contracture.  Muscle  exposed  in  a  solution  of  potassic  chlo- 
ride dies  very  much  sooner  than  in  an  isotonic  solution  of  sodium  chloride. 

Chloride  of  potash  has  also  some  depressant  action  on  the  peripheral 
nerves,  for  they  lose  their  irritability  rapidly  when  they  are  exposed  to  its 
solutions.  A  concentrated  solution  applied  to  an  exposed  nerve  causes  con- 
tractions of  the  muscles  which  are  supplied  by  it,  but  these  are  weaker 
and  last  a  much  shorter  time  than  those  elicited  by  a  similar  solution  of 
common  salt.  This  is  explained  by  the  depressant  action  of  the  potassium 
opposing  the  irritation  which  it  induces  through  its  salt-action.  This  effect 
on  the  nerves  has  been  used  by  Pohl  to  explain  a  curious  observation  made 
by  Nothnagel,  who  found  that  a  strong  solution  of  chloride  of  sodium  ap- 
plied to  the  peritoneal  surface  of  the  rabbit's  intestine,  causes  a  local  con- 
traction, followed  by  an  upward  peristaltic  wave,  while  a  similar  solution  of 
a  potassium  salt  induces  only  local  contraction.  Pohl  supposes  that  in  the 
case  of  the  sodium  salt  the  peristaltic  wave  is  caused  by  nerve  stimulation, 
while  the  potassium  depresses  the  nerve  so  much  that  it  is  unable  to  carry 
the  impulses,  and  the  contraction  therefore  remains  local. 

The  absorption  of  potassium  salts  is  followed  by  the  same  changes  in  the 
movement  of  the  fluids  of  the  body  as  have  been  described  in  the  case  of 
sodium  chloride  (page  489).  This  generally  results  in  diuresis  with  an  in- 
crease in  the  potassium  and  the  sodium  and  chloride  in  the  urine.  It  is  often 
stated  that  the  potassium  salts  induce  a  more  marked  increase  in  the  urine 
than  those  of  sodium,  but  this  is  not  based  on  any  satisfactory  measurements  ; 
another  statement  which  requires  confirmation,  is  that  strong  solutions  of  po- 
tassic chloride  are  more  irritating  to  the  stomach  and  also  in  the  subcutane- 
ous tissues,  than  those  of  sodium  chloride ;  this  would  indicate  that  potassium 
has  a  specific  irritant  action  apart  from  its  salt-action,  which  is  not  unlikely, 
although  it  cannot  be  said  to  have  been  demonstrated  satisfactorily  as  yet. 

BIBLIOGRAPHY. 

See  also  Salt-action  (p.  485)  and  Sodium  Chloride  (p.  493). 

Bunge.     Pfliiger's  Arch.,  iv.,  p.  235.     Handbuch  der  physiol.  Chem.,  p.  107. 

Braun.     Pfliiger's  Arch.,  ciii.,  p.  476. 

Martin.     Amer.  Journ.  of  Physiol.,  xi.,  p.  370. 

Pohl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv.,  p.  95. 

Limbourg.     Ibid.,  xxiv.,  p.  342. 

Ringer.     See  the  bibliography  given  under  Calcium. 

DogieL     Centralbl.  f.  d.  med.  Wiss.,  1892,  p.  354. 

Brunton  and  Cash.     Phil. 'Trans.  Roy.  Soc.,  1884,  Part  1,  p.  197. 

Lithium,  Caesium,  Rubidium. 

In  regard  to  the  action  of  the  rarer  alkalies,  Lithium,  Cesium  and  Rubid- 
ium,1 comparatively  little  is  known.  They  seem  to  have  some  effect  in  de- 

1  The  still  rarer  metals  Yttrium,  Erbium,  Beryllium,  Didymium  and  Lanthanum 
have  scarcely  received  examination  except  at  the  hands  of  Brunton  and  Cash,  and  are 
not  of  sufficient  importance  to  require  further  mention  here. 


496  INORGANIC  SALTS,   ACIDS  AND  BASES. 

pressing  the  spinal  cord  in  the  frog,  but  it  is  uncertain  whether  this  is,  like 
the  action  of  sodium  chloride,  merely  due  to  the  presence  of  large  quantities 
of  salts  in  the  body,  or  whether  they  have  a  specific  action  on  the  nerve  cells. 
Lithium  seems  to  have  some  further  depressant  action  on  the  motor  nerves, 
and  to  weaken  the  muscular  contraction.  It  acts  much  less  powerfully  on 
the  mammalian  heart  than  potassium,  but  has  some  effect  in  weakening  it. 
Its  chief  effects  are  exercised  in  the  alimentary  tract,  for  gastro-enteritis  and 
extravasations  of  blood  into  the  stomach  and  bowel  are  induced  by  its  sub- 
cutaneous or  intravenous  injection  and  these  are  the  cause  of  death  in  fatal 
poisoning  in  animals.  Such  violent  effects  are  less  easily  elicited  by  the  ad- 
ministration of  lithium  by  the  mouth,  though  vomiting  and  purging  have  been 
caused  in  animals  by  this  method  also,  and  disturbance  of  the  alimentary  tract 
has  sometimes  followed  lithium  treatment  in  man.  Some  of  the  lithium  is 
excreted  in  the  bowel,  and  in  this  respect  this  metal  appears  to  form  a  contrast 
to  potassium  and  sodium  and  to  resemble  rather  the  group  of  alkaline  earths. 

Rubidium  seems  to  act  on  the  frog's  heart  and  on  muscle  cells  in  much  the 
same  way  as  potassium. 

Csesium  resembles  lithium  in  causing  inflammatory  reactions  in  the  alimentary 
tract,  leading  to  vomiting  and  diarrhoea,  when  it  is  injected  hypodermically  or 
when  large  doses  are  given  by  the  mouth.  It  is  partly  excreted  along  the  ali- 
mentary tract  in  mammals.  In  the  frog  it  induces  weakness  of  the  muscles  and 
paralysis. 

BIBLIOGRAPHY. 

Dietrich  u.  Harnack.     Arch.  f.  exp.  Path.  u.  Pharm.,  xix.,  p.  153. 
Brunton  and  Cash.     Phil.  Trans.  Roy.  Soc.,  1884,  p.  197. 
Binet.     Comptes  rendus  de  1' Academic,  cxv.,  p.  251. 

Eichet.  Arch.  de.  Physiol.,  1886,  i.,  p.  101.  Trav.  d.  Laborat.  de  Physiol.,  1893, 
ii.,  p.  398. 

Blumcnthal.     Pfliiger's  Arch.,  Ixii.,  p.  513. 

Winkler.     Ibid.,  Ixxi.,  p.  395.  ^ 

Good.     Amer.  Journ.  Med.  Sciences,  cxxv.,  p.  273  (lithium). 

Hanford.     Amer.  Journ.  of  Physiol.,  ix.,  p.  214  (caesium). 

III.     AMMONIUM. 

Although  ammonium  is  not  a  metal,  its  behavior  in  the  body  resem- 
bles in  many  points  that  of  the  fixed  alkalies,  and  it  may  therefore 
best  be  studied  along  with  them.  The  ordinary  solutions  of  ammonia, 
and  the  gas  itself  are  possessed  of  powerful  irritant  properties,  and  its 
general  action  can  be  determined  only  by  the  examination  of  those  of 
its  salts  in  which,  as  in  ammonium  chloride,  the  effects  of  the  anion 
can  be  neglected.  The  action  of  chloride  of  ammonium  is  due  to  the 
specific  action  of  the  base  and  to  the  salt-action. 

Action.  —  Its  most  striking  effect  is  the  stimulation  of  the  Central 
Nervous  System,  which  is  induced  when  it  is  injected  subcutaneously 
or  intravenously.  The  reflex  irritability  is  much  increased,  and  this 
may  be  followed  by  tetanic  convulsions  both  in  frogs  and  mammals. 
These  convulsions  persist  after  division  of  the  cervical  spinal  cord  and 
destruction  of  the  medulla  oblongata  and  brain,  and  are  evidently 
caused  by  changes  in  the  spinal  cord,  similar  to  those  met  with  in 
strychnine  poisoning.  According  to  Yourinsky,  the  increased  reflex 
and  the  convulsions  are  preceded  by  a  short  stage  of  depression  in  the 
frog  and  pigeon,  but  this  depression  is  not  observed  when  the  parts  of 
the  central  nervous  system  above  the  cord  are  destroyed  in  the  frog, 
or  when  the  cerebrum  is  removed  in  the  pigeon.  He  holds  that  the 


AMMONIUM.  497 

brain  is  first  stimulated,  and  that  this  action  inhibits  the  reflexes,  but 
that  as  the  stimulation  passes  downwards,  the  spinal  cord  is  acted  on 
in  turn  and  the  reflexes  are  exaggerated.  The  medullary  centres  are 
also  involved,  for  the  respiration  very  often  ceases  for  a  moment,  and 
then  becomes  very  much  accelerated,  and  in  some  instances  deeper. 
The  cause  of  the  altered  breathing  is  a  stimulation  of  the  respiratory 
centre ;  the  preliminary  pause  is  attributed  by  some  to  action  on  the 
vagus  ends  in  the  lungs,  but  this  is  denied  by  others,  and  it  seems  pos- 
sible that  it  is  due  to  excessive  stimulation  of  the  respiratory  centre. 

The  blood-pressure  rises  from  contraction  of  the  peripheral  arterioles, 
induced  by  stimulation  of  the  vaso-motor  centre,  while  the  heart  is 
sometimes  slowed  from  increased  activity  of  the  inhibitory  centre,  but  is 
said  to  be  accelerated  in  other  cases ;  whether  this  arises  from  action 
on  the  cardiac  muscle  or  on  the  accelerator  centre  is  still  unknown. 

During  the  convulsions,  the  respiration  is  arrested  and  the  blood- 
pressure  becomes  extremely  high*  If  large  enough  quantities  be  in- 
jected, the  stimulation  is  followed  by  paralysis  of  the  central  nervous 
system  and  the  animal  dies  of  asphyxia,  but  if  artificial  respiration  be 
carried  on  it  recovers  rapidly,  from  the  salt  being  changed  to  an  inac- 
tive substance  in  the  tissues. 

In  the  frog  ammonium  chloride  tends  to  paralyze  the  terminations  of 
the  Motor  Nerves,  but  little  or  no  such  action  is  met  with  in  mammals. 
This  marked  curara-like  action  differentiates  the  ammonium  tetanus  of 
the  frog  from  that  seen  under  strychnine,  as  the  spasms  last  a  shorter 
time,  and  soon  become  weaker  from  the  impulses  failing  to  reach  the 
muscles  through  the  depressed  terminations.  The  Muscles  themselves 
are  also  acted  on  by  ammonium  in  much  the  same  way  as  by  potassium, 
although  in  the  case  of  ammonium  a  preliminary  stage  of  somewhat 
augmented  irritability  has  been  observed  by  some  investigators.  Am- 
monium chloride  is  generally  credited  with  acting  on  the  Secretions  of 
the  stomach  and  of  the  bronchial  mucous  membrane,  which  it  is  said 
to  render  more  fluid  and  less  tenacious,  and  at  the  same  time  to  increase 
considerably.1  No  explanation  of  this  effect  on  the  mucous  secretion 
has  been  offered,  and  ammonia  does  not  seem  to  be  excreted  by  the 
lungs,  nor  has  it  been  found  in  the  bronchial  secretion. 

Ammonium  salts  penetrate  most  cells  of  the  body  more  freely  than 
the  salts  of  the  fixed  alkalies,  and  solutions  of  ammonium  chloride  are 
therefore  absorbed  more  rapidly  from  the  stomach  and  intestine  than 
those  of  sodium  or  potassium  chloride.  They  permeate  into  the  blood 
cells  with  still  greater  freedom,  and,  in  fact,  solutions  of  the  chloride 
of  ammonium  meet  with  little  more  resistance  in  entering  the  red  blood 
corpuscles  than  does  distilled  water.  If  ammonium  be  combined  with 
a  non-permeating  ion  it  penetrates  the  blood  cells  or  the  intestinal 
epithelium  with  difficulty,  however,  so  that  the  sulphate  of  ammonium 
is  slightly  cathartic,  although  less  so  than  the  sulphates  of  the  fixed 
alkalies.  (See  Saline  Cathartics.)  The  epithelium  of  the  lungs  appears 

1  Rossbach  states  that  the  injection  of  the  chloride  into  the  vein  of  an  animal  lessens 
the  bronchial  secretion. 
32 


498  INORGANIC  SALTS,  ACIDS  AND  BASES. 

to  be  impermeable  by  the  ammonium  ion,  so  that  when  ammonia  is 
inhaled  it  does  not  reach  the  blood,  and  when  it  is  absorbed  from  the 
alimentary  tract  it  does  not  appear  in  the  breath  (Magnus). 

When  ammonium  salts  are  taken  by  the  mouth,  they  have  little  or 
no  tendency  to  cause  symptoms  from  either  the  central  nervous  system 
or  the  heart.  No  case  is  known  in  which  convulsive  attacks  could  be 
shown  to  be  due  to  the  direct  action  on  the  central  nervous  system  in 
man,  and  it  is  very  doubtful  whether  the  circulation  is  aifected  at  all. 
In  some  cases  of  poisoning  with  ammonium  hydrate,  convulsions  have 
occurred,  but  these  seem  to  be  due  to  the  violent  local  action  of  the 
caustic  alkali.  The  chloride  of  ammonium  may  induce  irritation  and 
vomiting  when  taken  in  large  quantities  into  the  stomach,  but  only 
through  its  action  as  a  salt. 

Ammonium  is  changed  to  urea  in  the  body  and  is  Excreted  in  this 
form  in  the  urine.  This  transformation,  which  probably  takes  place  in 
the  liver  chiefly,  proceeds  very  rapidly,  so  that  considerable  quantities 
of  some  salts  may  be  injected  slowly  into  a  vein  without  inducing  any 
symptoms  whatever.  The  urea  in  the  urine  would  therefore  tend  to 
be  increased  by  ammonia  if  other  factors  were  not  involved,  and  as  a 
matter  of  fact  this  occurs  in  the  herbivora.  In  carnivorous  animals  and 
in  man,  on  the  other  hand,  some  of  the  salts  of  ammonium  increase  the  ex- 
cretion of  urea,  while  others  apparently  increase  the  ammonium  salts  in 
the  urine.  Thus  the  carbonate  or  acetate  of  ammonium  is  excreted  as 
urea,  while  the  chloride  appears  to  be  excreted  unchanged.  This  differ- 
ence in  the  behavior  of  the  ammonium  salts  is  more  apparent  than  real, 
however.  As  a  matter  of  fact  the  ammonia  is  excreted  as  urea  in  each 
case,  but  the  acid  with  which  it  is  in  combination  may  conceal  this.  In 
the  case  of  the  carbonate  no  acid  is  freed,  and  the  same  is  true  of  the 
acetate,  which  is  oxidized  to  the  carbonate  in  the  tissues.  When,  how- 
ever, urea  is  formed  from  ammonium  chloride,  hydrochloric  acid  is  lib- 
erated in  the  tissues  and  would  act  as  a  poison,  were  it  not  neutralized  at 
once  by  ammonia  being  formed  in  the  tissues  themselves.  It  is  then  ex- 
creted by  the  urine  in  combination  with  this  freshly  formed  ammonia,1 
while  that  with  which  it  was  formerly  combined  appears  as  urea.  The 
formation  of  ammonia  in  the  tissues,  however,  withdraws  some  nitrogen 
which  would  ordinarily  have  formed  urea,  so  that  the  net  result  is  that 
the  urea  excretion  is  little  changed,  while  the  ammonia  of  the  urine  is 
much  increased.  The  carnivora  therefore  neutralize  the  hydrochloric 
acid  with  freshly  formed  ammonia.  The  herbivora  on  the  other  hand 
neutralize  it  with  fixed  alkali,  so  that  the  administration  of  ammonia 
always  increases  the  urea  excreted  by  them,  while  little  or  no  ammo- 
nia appears  in  the  urine  ;  at  the  same  time  the  fixed  alkalies  of  the 
blood  tend  to  become  neutralized,  and  this  may  give  rise  to  serious 
symptoms.  (See  Acids.) 

The  urine  is  often  increased  by  the  exhibition  of  ammonium  salts,  but 
not  always.  It  is  to  be  noted  that,  while  the  alkaline  salts  of  the  fixed 

1  In  some  cases  apparently  the  hydrochloric  acid  is  not  excreted  in  this  way  at  once 
but  goes  to  increase  the  acidity  of  the  gastric  juice. 


AMMONIUM.  499 

alkalies  render  the  urine  less  acid  or  even  alkaline,  ammonium  salts 
have  no  such  effect,  because  they  are  excreted  as  urea. 

In  birds  and  reptiles,  ammonia  is  apparently  excreted  as  uric  acid. 

The  Substituted  Ammonias  of  the  methane  series,  such  as  methylamine, 
and  some  of  those  of  the  aromatic  series  resemble  ammonia  in  their  general 
effects,  but  the  stimulation  of  the  central  nervous  system  is  not  often  so 
marked  a  feature.  In  general  terms,  those  compounds  in  which  one  hydro- 
gen atom  is  substituted,  tend  to  cause  greater  nervous  stimulation  than  those 
in  which  two  or  three  such  substitutions  are  made,  while  this  action  is  again 
more  prominent  in  those  in  which  four  alkyl  groups  are  combined  with  the 
nitrogen.  In  addition,  most  of  these  compounds  seem  to  have  a  more  depres- 
sant action  on  the  central  nervous  system  afterwards  than  ammonia,  and  they 
all  tend  to  weaken  and  eventually  paralyze  the  terminations  of  the  motor 
nerves. 

The  ammonium  bases  formed  from  the  natural  alkaloids  appear  to  have 
less  action  on  the  central  nervous  system,  but  act  like  curara  on  the  termina- 
tions of  the  motor  nerves.  (See  page  260.) 

PREPARATIONS. 

Ammonii  Chloridum  (U.  S.  P.,  B.  P.)  (NH.C1),  0.3-1  G.  (5-15  grs.),  in 
solution. 

Trochisci  Ammonii  Chloridi  (U.  S.  P.),  each  containing  0.1  G.  (2  grs.)  of 
ammonium  chloride  with  0.25  G.  (4  grs.)  of  liquorice  extract  and  some  syrup 
of  Tolu. 

Therapeutic  Uses.  —  The  chloride  is  prescribed  chiefly  for  its  effects 
on  the  respiratory  mucous  membranes,  and  is  a  very  common  constit- 
uent of  expectorant  mixtures  for  bronchitis  and  catarrh.  The  lozenge 
is  often  used  for  sore  throat,  and  chloride  of  ammonium  solutions  are 
occasionally  inhaled  or  sprayed  into  the  throat.  It  has  also  been  pre- 
scribed in  gastric  catarrh  with  benefit  in  some  cases,  but  whether  this 
is  due  to  its  acting  on  the  mucous  secretion,  or  to  its  increasing  the 
acidity  of  the  gastric  juice  is  unknown. 

Ammonium  chloride  and  the  chloride  of  trimethylammonium  were  at 
one  time  advised  in  rheumatism,  but  have  proved  useless  in  this  disease. 

BIBLIOGRAPHY. 

On  the  Action  of  the  Ammonium  ion. 

Lange.     Arch.  f.  exp.  Path.  u.  Pharm.,  ii.,  p.  364. 

Feltz  et  Ritter.     Journ.  de  1'Anat.  et  de  la  Physiol.,  1874,  p.  326. 

Funke.     Pfluger's  Arch.,  ix.,  p.  416. 

Binz.     Centralbl.  f.  klin.  Med.,  1888,  p.  25. 

Yowrinsky.     Arch.  d.  Sciences  biolog. ,  iii.,  p.  260. 

Bossbach.     Festschr.  zur  dritten  Saecularfeier,  Wiirzberg,  1882,  i.,  p.  85. 

Formanek.     Arch,  internat.  de  Pharmacodyn.,  vii.,  p.  229. 

Magnus.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliv  ,  p.  100. 

On  the  fate  of  ammonia  in  the  body. 

Schmiedeberg.     Arch.  f.  exp.  Path.,  viii.,  p.  1. 

Hallervorden.     Ibid.,  x.,  p.  125. 

Coranda.     Ibid.,  xii.,  p.  76. 

Knieriem.     Zeitschr.  f.  Biol.,  x.,  p.  263. 

Salkoivski.     Zeitschr.  f.  physiol.  Chem.,  i.,  p.  1. 

Marfori.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiii.,  p.  71. 

Rumpf  u.  Kleine.     Zts.  f.  Biol.,  xxxiv.,  p.  65. 

Pohl  u.  Munzer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xliii.,  p.  28. 


500  INORGANIC  SALTS,   ACIDS  AND  BASES. 

On  the  action  of  substituted  ammonias. 

Brunton  and  Cash.     Phil.  Trans.  Eoy.  Soc.,  1884,  i.,  p.  197. 
Nebelthau.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvi.,  p.  451. 

IV.     BROMIDES. 

It  was  formerly  widely  believed  that  the  bromides  had  DO  further 
action  than  the  chlorides,  and  that  any  effects  observed  from  potassium 
bromide  were  due  to  the  potassium  ion,  the  bromide  ion  being  indif- 
ferent. There  is  now  no  question,  however,  that  the  bromides  have 
distinctive  effects,  for  the  bromides  of  potassium,  sodium,  lithium,  and 
other  metals  induce  changes  in  the  central  nervous  system,  which  are 
not  elicited  by  the  chlorides.  At  the  same  time  the  bromide  action  is 
comparatively  weak,  and  the  basic  part  of  the  salt  has  therefore  con- 
siderable influence  on  the  action. 

Symptoms.  —  The  bromide  of  potassium  is  the  salt  most  generally 
used,  and  its  action  has  been  more  carefully  described  than  that  of  the 
other  bromides. 

In  the  Alimentary  Tract  it  acts  in  the  same  way  as  the  chloride  of 
sodium,  possessing  a  bitter  salt  taste  and  inducing  salivation  and 
thirst,  and  in  large  quantities,  irritation  of  the  stomach,  nausea  and 
vomiting.  Occasionally  diarrhoea  has  been  observed  from  concen- 
trated solutions  reaching  the  intestine. 

General  Symptoms.  —  Apart  from  these  results  of  local  irritation,  the 
first  symptom  is  often  a  dull,  heavy  headache,  with  a  feeling  of  lassi- 
tude, fatigue,  disinclination  for  exertion,  mental  or  physical,  and  often 
muscular  weakness.  Thought  is  slow  and  confused,  the  memory  is 
indistinct,  ideas  are  put  into  words  with  difficulty  and  the  speech  is 
accordingly  slow  and  hesitating.  External  objects  and  movements  are 
perceived,  but  arouse  no  interest  in  the  patient,  and  very  often  this 
state  of  apathy  passes  into  drowsiness  and  sleep.  The  bromides,  how- 
ever, have  not  the  sleep-compelling  power  of  morphine  or  chloral,  and 
the  sleep  is  never  very  deep  and  is  not  refreshing,  the  patient  some- 
times feeling  dull  and  unfit  for  exertion  after  it,  and  some  mental  con- 
fusion often  persisting  for  several  hours  after  awaking.  The  reflexes 
are  much  depressed  by  large  doses  of  bromide,  so  that  touching  the 
back  of  the  throat  does  not  induce  nausea,  although  the  sensation  of 
touch  may  persist.  The  mucous  membranes  of  the  genito-urinary 
tract  are  also  less  sensitive,  or  rather  their  irritation  is  less  liable  to 
set  up  reflex  movements.  After  very  large  doses  of  the  bromides  the 
conjunctiva  may  sometimes  be  touched  without  causing  winking,  and 
lessened  sensation  in  the  skin  has  been  noted  in  some  cases. 

The  pulse  is  slow  and  weak  after  large  doses  and  the  respiration  is 
also  less  active.  An  increase  in  the  urine  is  often  observed. 

Acute  fatal  poisoning  with  bromides  has  seldom  or  never  occurred 
in  man,  but  after  enormous  doses  prolonged  sleep  or  stupor  has  been 
seen,  and  confusion  and  apathy  lasting  for  several  days. 

When  bromide  is  given  repeatedly  in  large  doses,  a  series  of  symp- 
toms is  often  induced  to  which  the  name  of  Bromism  has  been  applied, 


BROMIDES.  501 

It  occurs  much  more  rapidly  in  some  persons  than  in  others,  and  may 
suddenly  appear  after  the  patient  has  been  taking  the  drug  for  months 
without  any  untoward  results.  The  commonest  symptoms  of  bromism 
are  akin  eruptions  of  various  kinds,  very  often  commencing  as  acne  of 
the  face.  In  severe  cases  the  pustules  of  acne  may  coalesce  and  form 
small  abscesses,  which  are  followed  by  ulcers.  In  other  cases  the  skin 
affection  partakes  rather  of  the  nature  of  a  localized  blush  or  erythema, 
and  sometimes  copper-colored  blotches  have  been  observed.  Some  dis- 
turbance of  the  digestion  and  loss  of  appetite  is  often  met  with  from  the 
local  action  of  large  quantities  of  the  salt  on  the  stomach.  Affections 
of  the  respiratory  passages  are  not  produced  so  often  by  the  bromides 
as  by  the  iodides,  but  have  been  met  with  and  consist  in  an  increased 
secretion  of  mucus  by  the  bronchial  and  nasal  epithelium.  The  mental 
symptoms  are  merely  exaggerations  of  those  observed  after  one  large 
dose.  The  memory  is  especially  defective,  sometimes  sudden  lapses 
occurring,  sometimes  a  general  inability  to  remember  the  most  recent 
events  being  met  with.  The  patient  is  indifferent  to  his  surroundings, 
speaks  slowly  and  stammers,  mispronounces  ordinary  words,  or  misses 
several  words  out  of  a  sentence.  The  gait  is  uncertain  and  tremor 
often  accompanies  any  movement,  the  expression  of  the  face  is  stupid 
and  apathetic,  and  the  eyes  are  heavy  and  lack  lustre. 

These  symptoms  generally  disappear  on  the  withdrawal  of  the  drug, 
but  in  his  reduced  condition  the  patient  is  of  course  liable  to  fall  a 
victim  to  infectious  disease,  and  in  a  number  of  cases  of  chronic 
bromide  poisoning  the  immediate  cause  of  death  has  been  an  attack 
of  bronchitis  or  pneumonia. 

Action.  —  The  effects  of  the  bromides  on  animals  have  been  the  sub- 
ject of  a  large  number  of  researches,  but  these  have  not  been  attended 
with  success  in  most  cases,  because  the  investigators  have  almost 
always  used  the  bromide  of  potassium.  The  action  here  is  complicated 
by  the  potassium  action  as  well  as  by  the  salt-action,  and  these  are 
often  sufficient  to  obscure  the  slight  depression  of  the  brain  which  is 
the  really  characteristic  effect  of  the  bromide  ion.  In  the  frog,  for 
example,  potassium  chloride  is  capable  of  inducing  depression  of  the 
central  nervous  system,  and  a  certain  amount  of  stupor  is  induced  by 
the  salt  action  of  chloride  of  sodium.  The  slightly  greater  depression 
induced  by  the  bromide  may  well  be  overlooked,  therefore,  and  many 
investigators  have  concluded  that  the  bromide  ion  is  as  inactive  as  the 
chloride.  The  typical  bromide  action  may  be  induced  with  greater 
clearness  in  mammals  by  the  use  of  sodium  bromide  in  repeated  doses, 
and  in  dogs  symptoms  of  depression  and  imperfect  coordination  have 
been  observed,  and  sometimes  stupor  and  death  from  failure  of  the 
respiration.  The  most  characteristic  action,  however,  is  obtained  from 
the  administration  of  the  drug  to  patients,  as  the  affection  of  the  cen- 
tral nervous  system  is  so  slight  after  all  but  extreme  doses,  that  in 
order  to  produce  distinct  symptoms  in  the  less  sensitive  brain  of  the 
dog,  quantities  must  be  used  which  entail  the  additional  complication 
induced  by  salt-action. 


502  INORGANIC  SALTS,  ACIDS  AND  BASES. 

The  irritation  of  the  throat  and  stomach,  the  nausea,  vomiting,  and 
rarer  diarrhoea  must  be  attributed  for  the  most  part  to  the  action  of 
the  salt  in  withdrawing  fluid  from  the  mucous  membranes,  and  may 
be  avoided  by  the  use  of  dilute  solutions  and  by  their  administration 
when  the  stomach  is  full. 

The  depression  and  other  mental  symptoms  are  due  to  a  direct  action 
on  the  Central  Nervous  System.  Albertoni  found  that  the  irritability 
of  the  motor  areas  of  the  dog's  brain  was  very  distinctly  reduced  by 
the  administration  of  bromides,  and  in  particular  that  a  stimulus  which 
normally  would  have  spread  over  a  wide  area  and  given  rise  to  an 
epileptiform  convulsion,  caused  only  localized  contractions  after  bro- 
mides, while  convulsive  poisons  entirely  failed  to  act.  Loewald  found 
some  psychical  processes,  such  as  those  involved  in  the  addition  of 
numbers,  uninfluenced  by  bromides,  while  a  series  of  figures  could  be 
learned  by  rote  only  with  great  difficulty ;  he  therefore  considers  that 
the  action  is  limited  to  certain  definite  functions.  The  reflexes  are 
also  reduced  very  considerably  by  bromides,  and  according  to  many 
observers  this  occurs  in  the  frog  before  the  spontaneous  movements 
cease.  This  is  explained  by  the  passage  of  impulses  from  the  sensory 
to  the  motor  cells  of  the  cord  being  interrupted,  while  the  connection 
between  the  cerebral  centres  and  the  motor  cells  of  the  cord  is  main- 
tained intact.  The  reflexes  in  man  are  prevented  or  retarded  also,  the 
most  striking  instance  being  the  absence  of  reflex  nausea  when  the 
back  of  the  throat  is  touched.  The  other  reflexes  are  also  reduced, 
especially  those  of  the  genital  organs,  those  of  the  conjunctiva  being 
less  affected.  While  reflex  movements  cannot  be  elicited,  the  sensa- 
tion often  remains  unimpaired,  but  after  large  doses  a  more  or  less 
complete  anaesthesia  is  said  to  be  produced.  This  anaesthesia  extends 
to  the  skin  when  very  large  quantities  are  administered,  and  the  cuta- 
neous nerves  are  said  to  be  rendered  somewhat  less  acutely  sensitive, 
when  comparatively  small  doses  are  taken. 

The  depression  of  the  spinal  reflexes  effected  by  the  bromides  ren- 
ders them  antidotal  to  strychnine,  which  induces  convulsions  only  when 
given  in  much  larger  quantities  than  are  usually  necessary. 

In  addition  to  the  ordinary  reflexes,  some  special  functions  are  de- 
pressed by  the  bromides.  Thus  the  respiration  becomes  slower,  and 
the  sexual  instincts  are  depressed  or  entirely  suspended  in  many  cases. 
Whether  the  latter  is  caused  by  action  on  the  spinal  cord  or  on  the 
cerebral  cortex  is  unknown. 

The  action  on  the  central  nervous  system  is  due  to  the  bromide 
only,  and  not  to  the  base  with  which  it  is  combined.  Thus,  it  may  be 
elicited  by  the  bromides  of  potassium,  sodium,  lithium  or  ammonium, 
while  it  is  not  induced  by  their  chlorides. 

The  bromide  ion  is  not  very  poisonous  to  Nerve  and  Muscle,  but  it  is 
not  so  nearly  indifferent  to  them  as  the  chloride  ion,  although  no  effects 
are  elicited  unless  the  bromide  is  applied  directly  to  the  exposed  mus- 
cle or  nerves. 

The  Cardiac  Effects,  when  present,  arc  caused  by  the  potassium  com- 


BROMIDES.  503 

ponent  only,  and  are  not  elicited  by  the  bromides  of  sodium  and  am- 
monium. The  vessels  of  the  pia  mater  are  often  found  contracted  from 
the  action  of  bromides,  and  this  has  been  supposed  to  account  for  the 
depression.  It  is  probable,  however,  that  this  anemia  of  the  brain  is 
analagous  to  that  observed  in  sleep  and  it  may  therefore  be  the  result 
and  not  the  cause  of  the  depression.  The  mental  disturbance  observed 
in  bromism  is  so  nearly  related  to  that  seen  after  a  single  large  dose, 
that  it  is  unnecessary  to  enter  into  any  explanation  of  it  here. 

The  Skin  Eruptions  have  usually  been  attributed  to  the  excretion  of 
bromide  through  the  cutaneous  glands,  and  seem  to  arise  in  the  great 
majority  of  cases  from  the  glands,  and  in  fact  generally  remain  con- 
fined to  them.  Bromide  has  been  found  in  the  acne  pustules,  and  it  is 
quite  conceivable  that  it  may  act  as  an  irritant  here,  especially  when 
the  secretion  becomes  acid  from  decomposition. 

The  Temperature  of  animals  is  often  said  to  be  reduced  by  the  bro- 
mide ;  this  may  be  explained  by  the  lessened  movement. 

Excretion.  —  The  bromides  are  rapidly  absorbed  by  the  mucous 
membranes,  and  some  bromide  reaction  can  be  obtained  from  the  urine 
a  few  minutes  after  they  have  reached  the  stomach,  but  the  great  mass 
of  the  drug  is  very  slowly  excreted.  When  the  treatment  is  continued, 
the  bromide  therefore  tends  to  accumulate  in  the  body,  but  the  pro- 
portion excreted  rises  with  the  increase  of  the  salt  in  the  blood,  until 
an  equilibrium  is  reached,  exactly  as  much  bromide  appearing  in  the 
urine  as  is  absorbed  from  the  stomach.  The  excretion  continues  after 
the  treatment  is  discontinued,  and  the  drug  is  found  in  the  urine  for 
one  or  two  months  afterwards.  When  the  body  is  thus  saturated  with 
bromides,  some  of  the  chloride  combinations  are  replaced  by  them  ; 
for  example,  Nencki  found  that  the  acid  secreted  by  the  stomach  might 
contain  more  hydrobromic  than  hydrochloric  acid.  The  substitution 
of  bromide  for  chloride  may  be  the  cause  of  some  of  the  symptoms  of 
bromism  ;  one  consequence  is  that  the  chlorides  released  from  their 
combinations,  are  excreted  in  much  larger  quantity  than  usual  in  the 
urine.  The  nitrogenous  metabolism  does  not  seem  to  be  affected,  but 
in  some  cases  a  considerably  smaller  amount  of  phosphates  appears 
in  the  urine.  This  has  been  supposed  to  be  related  to  the  action  of 
bromides  in  lessening  the  mental  activity,  but  is  not  by  any  means  a 
constant  effect. 

The  bromides  seem  to  be  distributed  in  the  body  very  much  in  the 
same  proportion  as  the  chlorides,  being  most  largely  found  in  the 
blood  serum,  while  the  brain  and  spinal  cord  contain  them  in  com- 
paratively small  proportion. 

The  bromides  are  excreted  mainly  in  the  urine,  but  traces  occur 
in  the  perspiration  and  milk,  and  some  cases  of  bromism  in  children 
have  been  recorded  as  due  to  their  absorbing  the  bromide  thus  ex- 
creted by  the  nurse.  In  chronic  poisoning  the  breath  very  often  has 
a  disagreeable  odor,  which  has  been  attributed  to  bromine  or  some  of 
its  volatile  organic  compounds  being  excreted  by  the  lungs,  but  noth- 
ing is  known  with  certainty  regarding  it.  Bromine  has  also  been 


504  INORGANIC  SALTS,  ACIDS  AND  BASES. 

found  in  the  hair  after  the  prolonged  use  of  bromides,  and  is  supposed 
to  exist  in  organic  combinations  here.  The  hydrobromic  acid  secreted 
into  the  stomach  in  bromism  is  probably  all  reabsorbed  in  the  intestine. 

Bromide  of  Sodium  differs  from  bromide  of  potassium  chiefly  in  the 
absence  of  any  changes  in  the  heart  or  in  the  muscles  exposed  to  its 
solution.  The  central  nervous  system  also  seems  somewhat  less  de- 
pressed, because  the  potassium  in  itself  has  some  effect,  while  the 
sodium  ion  is  indifferent. 

Bromide  of  Ammonium  owes  most  of  its  action  to  the  bromide  ion, 
unless  when  it  is  given  in  large  quantities,  when,  according  to  several 
observers,  the  convulsive  action  characteristic  of  ammonium  is  devel- 
oped in  animals.  Smaller  doses  are  followed  by  lethargy  and  weak- 
ness in  animals,  and  in  man  the  effects  are  practically  identical  with 
those  of  sodium  bromide. 

Lithium  Bromide  has  not  been  so  largely  used  as  the  others,  and  is 
liable  to  cause  digestive  disturbances  from  the  lithium  action  (see  p.  495). 

Hydrobromic  Acid  possesses  the  characteristic  bromide  action  after 
absorption,  but  has  the  local  action  of  an  acid  and  is  consequently 
more  irritant  than  the  other  members  of  the  series. 

Strontium  and  Calcium  Bromides  seem  to  resemble  the  others  in  their 
general  action  and  are  said  to  disturb  the  digestion  less.  At  the  same 
time  calcium  and  strontium  salts  are  generally  absorbed  more  slowly 
by  the  intestine  than  those  of  the  alkalies. 

PREPARATIONS. 

POTASSII  BROMIDUM  (U.  S.  P.,  B.  P.)  (KBr),  1-4  G.  (15-60  grs.). 

SODII  BROMIDUM  (U.  S.  P.,  B.  P.)  (NaBr),  1-4  G.  (15-60  grs.). 

Ammonii  Bromidum  (U.  S.  P.,  B.  P.)  (NH4Br),  1-2  G.  (15-30  grs.). 

Liihii  Bromidum  (U.  S.  P.)  (LiBr),  1-2  G.  (15-30  grs.). 

Calcii  Bromidum  (U.  S.  P.)  (CaBr2),  2-4  G.  (30-60  grs.). 

Strontii  Bromidum  (U.  S.  P.)  (SrBr2),  2-4  G.  (30-60  grs.). 

Acidum  Hydrobromicum  Dilutum  (U.  S.  P.,  B.  P.)  contains  comparatively 
little  bromide,  as  it  is  only  a  10  per  cent,  solution  in  water,  so  that  a  gramme 
of  bromide  of  potash  contains  as  much  bromine  as  about  7  grammes  of  the 
dilute  acid.  6-12  c.c.  (J-3  fl.  drs.)  (B.  P.,  15-60  mins.). 

The  bromides  are  all  colorless  crystalline  bodies  without  odor  but  with  a 
saline,  bitter  taste,  and  are  very  soluble  in  water  They  are  almost  always 
prescribed  in  solution  and  ought  to  be  taken  diluted  with  a  considerable 
amount  of  water  in  order  to  avoid  the  irritant  action  on  the  stomach.  The 
prescription  may  be  flavored  with  syrup  and  with  some  of  the  volatile  oil 
preparations.  The  large  doses  of  the  bromides  render  their  hypodermic  in- 
jection inadmissible,  as  concentrated  solutions  provoke  pain  and  irritation  in 
the  subcutaneous  tissues. 

A  number  of  other  bromide  combinations  are  used  in  therapeutics,  such  as 
the  hydrobromate  of  quinine,  but  here  the  bromide  ion  is  present  in  very 
small  quantity  compared  with  the  alkaloid,  and  in  the  doses  used  in  ther- 
apeutics has  no  appreciable  effect.  In  monobromated  camphor  the  bro- 
mine is  present  in  a  different  form  and  no  bromide  ion  is  liberated,  so  that 
the  action  of  the  metallic  bromides  cannot  be  compared  with  it.  As  a 
matter  of  fact,  the  bromine  in  this  compound  seems  to  have  little  or  no 
effect. 

Therapeutic  Uses.  —  The  bromides  are  used  chiefly  in  the  treatment 
of  epilepsy,  in  which  they  cannot  be  replaced  by  any  other  drug,  and 


BROMIDES.  505 

the  prognosis  of  which  has  been  entirely  changed  since  their  introduc- 
tion. In  a  few  cases  the  bromide  treatment  is  said  to  cure  epilepsy  — 
the  attacks  do  not  return  after  the  treatment  is  stopped  —  but  this  is 
exceedingly  rare ;  in  others  the  bromides  have  no  effect,  but  in  the 
great  majority  of  cases  (90-95  per  cent.)  the  number  of  attacks  is 
much  smaller,  or  the  patient  may  be  entirely  free  from  them  as  long  as 
the  treatment  is  persevered  with,  although  they  return  as  soon  as  it  is 

tiven  up.  Very  often  no  improvement  is  observed  during  the  first 
i\v  days,  until  the  tissues  have  become  saturated  with  bromide,  but  in 
other  cases  the  spasms  disappear  immediately.  The  bromide  of  potas- 
sium is  more  commonly  used  than  the  others,  and  the  general  impres- 
sion is  that  it  is  more  efficient  and  more  certain  in  its  effects,  but  some 
physicians  prefer  the  bromide  of  ammonium  or  of  lithium,  and  others 
still  prefer  a  mixture  of  two  bromides.  In  severe  eases  it  is  some- 
times found  that  the  bromide  action  is  strengthened  by  the  addition  of 
cannabis  indica,  opium  or  chloral,  although  the  last  two  are  to  be  used 
with  caution.  In  the  treatment  of  epilepsy  it  is  well  to  begin  with 
small  doses  and  to  increase  them  up  to  10  G.  per  day,  or  until  the  de- 
sired effect  is  attained,  or  some  complication,  such  as  widespread  skin 
affections,  precludes  their  further  use.  When  little  chloride  is  taken  in 
the  food  the  excretion  of  bromide  is  much  retarded,  and,  on  the  other 
hand,  the  addition  of  chloride  to  the  dietary  accelerates  the  bromide 
excretion.  The  restriction  of  the  salt  in  the  food  of  epileptics  under 
bromide  treatment  has  therefore  been  suggested  with  the  object  of 
saturating  the  tissues  with  smaller  doses  of  bromide  than  would  other- 
wise be  necessary.  In  practice,  however,  it  is  difficult  to  reduce  mate- 
rially the  chlorides  of  the  food,  and  equally  satisfactory  results  may  be 
obtained,  with  less  hardship  to  the  patient,  by  slightly  increasing  the 
dose  of  bromide. 

The  acne  is  very  often  a  troublesome  accompaniment  of  the  bromide 
action,  and  in  fact  may  prevent  the  use  of  this  valuable  drug  in  other- 
wise suitable  cases.  It  may  often  be  prevented  by  scrupulous  clean- 
liness of  the  skin  and  frequently  yields  to  treatment  with  small  doses 
of  arsenic. 

The  bromides  are  not  so  effective  in  other  affections  of  the  central 
nervous  system,  although  some  success  has  attended  their  use  in  chorea, 
in  the  convulsions  of  children,  and  in  some  forms  of  hysteria.  They 
have  also  been  used  in  tetanus  and  in  strychnine  poisoning,  but  are 
inferior  to  other  remedies  such  as  chloral.  Neuralgia  is  sometimes 
improved  by  bromide  treatment,  especially  when  it  arises  from  worry, 
anxiety,  or  overwork. 

As  soporifics,  bromides  often  fail  entirely,  or  induce  such  depression 
and  confusion  subsequently  as  to  preclude  their  use.  In  sleeplessness 
from  anxiety,  they  are  often  valuable,  however,  and  it  is  found  that 
the  dose  of  chloral  may  be  considerably  lessened,  if  it  is  prescribed 
along  with  bromides.  In  sleeplessness  from  pain,  bromide  is  of  little 
or  no  value. 

Bromides  have  been  used  with  good  results  in  sea-sickness,  in  the 


506  INORGANIC  SALTS,  ACIDS  AND  BASES. 

sickness  of  pregnancy,  and,  it  is  said,  in  whooping-cough.  Bromide 
of  potash  was  formerly  given  internally  to  lessen  the  reflex  movements 
of  the  throat  and  thus  to  permit  of  laryngoscopic  manipulations,  and 
it  was  also  applied  locally  to  the  throat  for  this  purpose.  It  has  now 
been  superseded  by  the  local  use  of  cocaine. 

THE  BIBLIOGRAPHY 

of  potassium  bromide,  up  to  1877,  is  given  fully  by 

Krosz.     Arch.  f.  exp.  Path.  u.  Pharm.,  vi.,  p.  1.     See  also 

Albertoni.     Ibid.,  xv.,  p.  248. 

Loewald.     Kraepelin's  Psych olog.  Arb.,  i.,  p.  489. 

Ach.     Ibid.,  iii.,  p.  203. 

Wiersma.     Ztsch.  f.  Psych,  u.  Phys.  d.  Sinnesorgane,  xxviii.,  p.  179. 

Nencki  u.  Schoumow-Simanowsly.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv.,  p.  313. 

Heftcr.     Ergebnisse  der  Physiologic,  ii.,  1,  p.  102. 

Bistroff.     Arch.  f.  Anat.  u.  Phys.,  1868,  p.  721.      (Ammonium  bromide.) 

Amory.     Bromide  of  Potassium  and  Bromide  of  Ammonium,  Boston,  1872. 

Wdr  Mitchell    American  Journ.  of  Med.  Sciences,  lx.,  p.  440.     (Lithium  bromide.) 

Heichert.     Boston  Med.  and  Surg.  Journ.,  civ.,  p.  505.     (Hydrobromic  acid.) 

Hosenthal.     Ztschr.  f.  phys.  Chem.,  xxii.,  p.  227. 

V.    IODIDES. 

Although  the  iodides  have  been  more  largely  used  in  medicine  than 
any  of  the  other  salts  of  the  alkalies,  their  mode  of  action  is  still 
wrapped  in  obscurity.  This  is  due  to  the  unsatisfactory  state  of  the 
pathology  of  the  diseases  in  which  they  are  used,  to  the  fact  that  the 
attention  of  investigators  has  been  drawn  to  the  symptoms  of  poison- 
ing rather  than  to  the  therapeutic  action,  and  also  to  the  fact  that  the 
effects  seem  to  vary  very  considerably  not  only  in  different  individuals, 
but  also  in  the  same  person  at  different  times. 

Symptoms.  —  Large  quantities  of  the  iodides  cause  irritation  of  the 
stomach  from  their  salt-action,  and  induce  nausea  and  vomiting,  more 
rarely  diarrhoea ;  but  these  symptoms  are  quite  distinct  from  those 
known  as  lodism,  which  may  arise  from  comparatively  small  quanti- 
ties, and  which  are  most  commonly  seen  when  the  remedy  has  been 
administered  repeatedly. 

The  commonest  symptom  of  iodism  is  catarrh  of  the  Respiratory 
Passages,  more  especially  of  the  nose,  which  betrays  itself  in  some 
swelling  and  discomfort  in  the  nasal  mucous  membrane,  in  a  profuse 
watery  secretion,  and  in  sneezing.  The  catarrh  spreads  upwards  to 
the  conjunctiva,  which  often  becomes  swollen  and  congested,  and  to 
the  frontal  sinuses,  where  it  induces  a  feeling  of  dulness  or  violent 
headache ;  it  also  progresses  downwards  to  the  tonsils,  which  become 
swollen  and  inflamed  in  some  cases.  Still  lower  it  occasionally  causes 
some  swelling  and  oedema  or  small  ulcers  in  the  larynx,  and  has  thus 
caused  dyspnoea,  which  has  necessitated  tracheotomy,  or  very  rarely 
has  proved  fatal.  Bronchitis  has  also  been  observed  in  man,  with  a 
profuse  watery  secretion,  and  in  animals  oedema  of  the  lungs  and 
pleuritic  effusion  have  been  produced  by  the  injection  of  iodides. 
Even  small  quantities  injected  intravenously  increase  the  mucus  se- 
creted by  the  bronchi. 


IODIDES.  507 

In  the  Mouth  iodism  is  often  betrayed  by  swelling  and  irritation  of  the 
throat  and  tonsils,  and  by  salivation,  rarely  by  swelling  of  the  salivary 
glands.  The  stomach  is  seldom  affected,  the  appetite  generally  remain- 
ing good,  but  in  some  persons  iodides  induce  nausea  and  gastric  dis- 
comfort. 

Skin  Eruptions  of  different  forms  are  also  common  results  of  the 
administration  of  iodides,  but  are  less  liable  to  occur  in  the  beginning 
of  the  treatment  than  the  catarrh  of  the  respiratory  passages.  These 
eruptions  may  simulate  almost  all  known  skin  diseases,  but  the  most 
common  forms  are  erythematous  patches,  or  papular  eruptions  which 
may  pass  into  pustules  or  into  larger  inflamed  areas.  Eczema,  bullse, 
pemphigus,  and  purpura  arise  less  frequently  from  the  use  of  iodides. 
In  some  cases,  a  more  or  less  defined  area  of  oedema  has  been  observed 
in  the  face. 

The  Secretion  of  Urine  is  generally  increased  by  the  administration 
of  iodides,  as  of  other  salts  of  the  alkalies,  though  they  seem  to  have 
no  specific  action  on  the  kidneys.  In  rare  cases  albuminuria  has  been 
observed,  and  some  irritation  of  the  bladder,  urethra,  and  vagina  is 
said  to  have  been  induced  by  iodide  treatment,  but  these  statements 
require  confirmation. 

Not  infrequently  the  Pulse  is  accelerated,  though  this  is  not  constant. 

The  Central  Nervous  System  seldom  seems  to  be  affected  by  the  treat- 
ment. In  rare  cases  paralysis,  tremors  and  various  disorders  of  sen- 
sation, such  as  localized  anaesthesia  or  neuralgic  pains,  have  been 
recorded,  but  it  seems  open  to  question  whether  these  were  in  all  cases 
the  direct  result  of  the  medication. 

A  slight  rise  of  Temperature  has  also  occurred,  often  apparently  from 
the  skin  affections  or  the  catarrh ;  in  some  doubtful  cases  apparently 
without  any  such  cause. 

Loss  of  Weight  has  been  noted  a  number  of  times  both  in  man  and 
animals.  This  is  seen  more  frequently  in  thyroid  disease  (goitre)  than 
elsewhere,  and  in  these  cases  the  goitre  is  often  reduced  in  size.  It  is 
still  disputed  whether  the  prolonged  use  of  iodides  lessens  the  size  of 
the  testicles  and  of  the  mammary  glands. 

In  some  rare  cases  of  very  prolonged  iodism,  a  Cachexia  has  been 
observed,  with  great  loss  of  flesh,  weakness,  depression,  mental  con- 
fusion, restlessness  and  aberrations  of  sensation.  These  did  not  disap- 
pear at  once  when  the  treatment  was  discontinued,,  as  the  ordinary 
symptoms  of  iodism  do. 

In  many  instances,  small  doses  of  iodide  may  be  given  repeatedly 
without  any  noticeable  disturbance,  but  in  others,  the  smallest  quantity 
(0.2  G.)  induces  severe  poisoning.  Some  authorities  consider  that 
these  small  doses  are  more  liable  to  cause  iodism  than  larger  ones,  but 
this  may  be  doubted,  as  the  action  of  the  drug  is  so  capricious,  that 
the  statistics  of  different  observers  show  great  discrepancies,  even 
when  approximately  the  same  dose  has  been  given.  Thus,  Haslund, 
treating  patients  with  at  first  3  G.  (45  grs.)  and  then  5  G.  (80  grs.) 
daily,  observed  iodism  in  only  12  per  cent,  of  his  cases  during  the  first 


508  INORGANIC  SALTS,  ACIDS  AND  BASES. 

few  days,  while  others  have  found  iodism  induced  in  60  per  cent,  of 
their  cases  after  a  single  dose  of  3  G.  An  attempt  has  been  made  to 
explain  these  discrepancies  by  supposing  that  iodism  is  only  produced 
by  impure  iodides,  but  this  is  not  correct,  for  it  has  been  observed  in 
numerous  cases  in  which  the  drug  was  absolutely  pure.  Among  other 
conditions  which  favor  the  onset  of  symptoms,  is  a  slow  excretion  of 
the  iodide  such  as  is  observed  in  some  forms  of  renal  irritation. 
Children  seem  less  liable  to  suffer  from  the  iodides  than  adults.  The 
dose  administered  has,  of  course,  some  relation  to  the  onset  of  symp- 
toms ;  thus,  very  large  doses  are  more  likely  to  induce  them  than  very 
small  ones,  but  it  seems  that  a  tolerance  is  soon  established  in  some 
cases,  for  after  iodism  has  been  induced,  and  the  daily  dose  lessened 
accordingly,  it  is  sometimes  found  that  it  may  be  gradually  increased 
until  a  quantity  considerably  greater  than  that  originally  given  may 
be  taken  with  impunity.  In  other  instances,  a  definite  quantity  may 
be  given  for  a  long  time  without  inducing  symptoms,  but  these  may  sud- 
denly set  in  without  any  apparent  change  in  the  treatment  and  without 
any  appreciable  cause.  Very  often  it  is  found  that  the  symptoms  dis- 
appear when  the  treatment  is  continued,  and  recovery  invariably  sets 
in  when  the  drug  is  abandoned.  The  iodides  all  induce  iodism,  the 
symptoms  being  apparently  unaffected  by  the  basic  ion,  but  the  iodide 
of  ammonium  is  said  to  be  more  liable  to  induce  them  than  the  others, 
owing  to  the  iodine  being  freed  from  it  more  easily.  The  symptoms 
are  seldom  dangerous,  but  a  few  cases  are  recorded  in  which  oedema 
of  the  larynx  resulted  and  proved  fatal,  and  in  others  death  was  attri- 
buted to  the  iodides,  but  the  exact  cause  was  not  ascertained. 

The  iodides  are  not  Absorbed  from  watery  solutions  applied  to  the 
skin,  but  are  rapidly  taken  up  by  all  the  mucous  membranes.  When 
given  by  the  mouth  they  are  absorbed  unchanged  by  the  stomach  and 
intestine,  and  appear  in  the  secretions  within  a  few  minutes.  The 
greater  part  of  the  iodide  is  Excreted  in  the  urine,  in  which  it  ap- 
pears as  salts.  Some  escapes  by  the  salivary  glands,  however,  and  small 
quantities  are  excreted  by  the  stomach  as  hydriodic  acid  and  some- 
times as  free  iodine ;  iodide  has  also  been  found  in  the  tears,  per- 
spiration, milk,  sebum,  and  in  the  secretion  of  the  nasal  mucous 
membranes.  No  iodine  can  be  detected  in  the  breath  of  animals 
poisoned  with  iodides.  After  treatment  with  iodide  of  potash,  iodine 
has  been  detected  in  the  hair,  milk,  muscles  and  heart  in  organic 
combination.  Iodides  are  much  more  rapidly  excreted  than  bromides, 
for  65-80  per  cent,  of  the  iodide  appears  in  the  urine  within  24  hours 
after  its  administration,  and  no  iodide  reaction  is  obtained  from  any  of 
the  secretions  a  week  after  the  treatment  has  ceased.  It  has  been  stated 
that  iodide  fails  to  pass  into  the  serous  cavities  in  inflammatory  transu- 
dates,  but  this  seems  to  be  incorrect,  although  the  starch  test  often 
fails  here  from  the  presence  of  proteids. 

The  greater  part  of  the  iodide  administered  therefore  passes 
through  the  tissues  and  is  excreted  in  the  urine  in  the  form  of  salts. 
If  iodide  of  potassium  be  given,  as  is  generally  the  case,  some  inter- 


IODIDES.  509 

change  between  it  and  the  salts  of  the  tissues  takes  place  and  iodide 
of  sodium,  chloride  of  potash  and  several  other  salts  are  formed,  and 
all  of  these  are  excreted  in  the  urine.  Some  of  the  iodide  undergoes 
decomposition  in  the  body,  however,  and  the  free  iodine  thus  formed 
is  believed  to  be  the  cause  of  the  symptoms  of  iodism.  This  decompo- 
sition of  iodides  in  the  body  was  at  first  rather  inferred  from  the  sim- 
ilarity of  the  symptoms  with  those  induced  by  iodine  preparations,  than 
from  the  actual  demonstration  of  the  presence  of  iodine  in  the  tissues. 
The  ordinary  iodine  tests  fail  in  albuminous  solutions,  because  it  ap- 
pears to  exist  in  a  loose  combination  with  the  proteids,  but  free  iodine 
has  been  shown  to  be  excreted  into  the  stomach,  and  an  organic  com- 
pound of  iodine  exists  in  the  hair  and  in  various  internal  organs  after 
iodide  treatment.  The  successful  treatment  of  goitre  with  iodide  of 
potassium  is  also  a  strong  argument  in  favor  of  the  presence  of  free 
iodine,  and  the  iodothyrin  of  the  thyroid  gland  has  been  shown  to  be 
increased  by  potassic  iodide.  When  iodine  is  thus  liberated  in  the 
body,  it  does  not  circulate  as  such,  but  at  once  combines  with  the  pro- 
teids. 

The  formation  of  free  iodine  from  iodides  (which  is,  of  course,  quite  dis- 
tinct from  their  dissociation  into  potassium  and  iodide  ions)  has  been  ex- 
plained by  several  theories.  The  first  of  these  assumed  that  the  iodide  was 
decomposed  by  the  carbonic  acid  of  the  blood,  forming  hydriodic  acid,  and 
that  this  was  subsequently  oxidized  in  the  blood  to  free  iodine.  Binz  sup- 
posed that  the  decomposition  occurred  rather  in  the  protoplasm  of  the  tis- 
sues, and  supported  his  statement  by  an  experiment  in  which  an  iodide  solu- 
tion was  saturated  with  carbonic  acid  and  had  plant  protoplasm  added  to  it, 
after  which  it  gave  the  ordinary  iodine  reaction  with  starch.  The  objection 
has  been  raised  that  this  experiment  succeeds  only  when  dying  protoplasm 
is  used,  and  another  theory  has  been  proposed,  namely,  that  the  oxidation 
is  carried  on,  not  by  the  protoplasm  itself,  but  by  some  unstable  substances 
which  are  excreted  by  living  matter,  and  which  therefore  occur  on  the  mucous 
membranes,  in  the  saliva  and  elsewhere.  These  bodies  are  in  themselves 
reducing  agents,  but  in  the  presence  of  air,  as  in  the  respiratory  passages, 
their  oxidation  is  accompanied  by  the  liberation  of  "active  oxygen"  which 
in  turn  oxidizes  the  iodides.  Another  explanation  which  has  been  given  for 
the  occurrence  of  free  iodine  is  the  action  of  nitrites,  which  decompose  iodide 
of  potassium  in  the  presence  of  acids.  But  Anten  found  that  iodism  is  not 
induced  more  readily  in  a  susceptible  subject  when  the  nitrites  are  augmented  in 
the  tissues.  It  has  been  stated  recently  that  iodism  is  very  readily  elicited  in 
patients  whose  saliva  contains  much  sulphocyanide,  and  that  the  occurrence  of 
this  body  in  the  secretions  of  the  respiratory  tract  is  responsible  for  the  manifes- 
tations of  irritation  induced  by  iodides.  Binz  has  found  that  some  microbes  are 
capable  of  setting  iodine  free  from  acid  solutions  of  the  iodides. 

Iodine  is  supposed  to  be  set  free  along  the  mucous  membrane  of  the 
respiratory  passages  and  in  the  skin  ;  and  in  this  way  the  coryza  of  the 
former,  and  the  eruptions  on  the  latter  are  explained.  It  must  be  noted 
that  free  iodine  has  not  yet  been  clearly  demonstrated  in  either  of  these 
surfaces,  and  that  the  theory  has  been  formulated  only  to  explain  the 
symptoms  of  iodism.  Iodides  have  been  found  in  the  nasal  secretion, 
saliva,  and  perspiration,  but  no  free  iodine.  Some  of  the  other  symp- 


510  INORGANIC  SALTS,  ACIDS  AND  £ASES. 

toms  of  iodism  are  probably  due  to  action  on  the  thyroid  gland;  thus 
the  acceleration  of  the  heart  observed  in  some  cases,  the  loss  of  flesh 
resulting  from  their  prolonged  use  in  others,  and  the  reduction  in  the 
size  of  goitres  may  all  be  explained  in  this  way.  (See  Thyroid  Extract.) 

The  central  nervous  system  and  the  circulation  scarcely  seem  to  be  affected 
by  iodides.  Very  large  quantities  of  potassic  iodide  injected  into  a  vein  are 
found  to  weaken  and  paralyze  the  heart  in  animals,  but  do  not  seem  to  be 
more  poisonous  than  other  potassium  salts,  and  depression  of  the  central 
nervous  system  may  also  be  elicited  in  the  same  way  by  the  potassium 
action.  Barbera  states  that  very  large  quantities  of  iodides  paralyze  the 
depressor  nerve  terminations  in  the  medulla  oblongata  and  weaken  the  pe- 
ripheral inhibitory  mechanism  of  the  heart,  while  Hunt  found  the  accelera- 
tor fibres  less  easily  fatigued  after  iodide.  The  metabolism  of  the  body 
seems  little  affected  by  iodides  in  most  cases,  but  a  further  examination  of 
the  excretions  of  patients  who  lose  weight  under  the  treatment  is  desirable. 
The  action  of  the  iodides  in  therapeutics  has  been  ascribed  by  some  authors 
to  their  rendering  the  movement  of  the  leucocytes  (diapedesis)  more  active, 
but  no  satisfactory  evidence  has  been  adduced  in  support  of  this.  Solutions 
of  iodide  of  sodium  are  found  to  be  more  poisonous  to  muscle,  cilia  and 
unicellular  organisms  exposed  to  them  than  are  similar  solutions  of  the 
chloride  or  bromide,  so  that  the  iodide  ion  appears  to  be  more  fatal  to 
protoplasm  than  the  bromide  and  chloride  ion,  while  it  is  less  poisonous  than 
the  fluoride.  In  the  frog  stiffness  and  awkwardness  in  the  movements  are 
elicited  by  comparatively  small  doses  of  iodide  of  sodium  and  these  symp- 
toms have  been  shown  to  be  due  to  rigor  mortis  occurring  in  the  muscles. 

PREPARATIONS. 

POTASSII  IODIDUM  (U.  S.  P.,  B.  P.)  (KI),  0.1-1.3  G.  (2-20  grs.). 

Unguentum  Potassii  lodidi  (U.  S.  P.,  B.  P.). 

Linimentum  Potassii  lodidi  cum  Sapone  (B.  P.). 

SODII  IODIDUM  (U.  S.  P.,  B.  P.)  (Nal),  0.1-1.3  G.  (2-20  grs.). 

Ammonii  lodidum  (U.  S.  P.)  (NH4I),  0.1-1  G.  (2-15  grs.). 

Strontii  lodidum  (U.  S.  P.)  (SrI2),  0.3-1  G.  (5-15  grs.). 

Syrupus  Acidi  Hydriodici  (U.  S.  P.),  a  syrup  containing  about  1  per  cent, 
by  weight  of  hydriodic  acid.  4  c.  c.  (1  fl.  dr.). 

Acidum  Hydriodicum  Dilutum  (U.  S.  P.),  10  per  cent.     0.5  c.c.  (8  mins.). 

The  iodides  form  colorless  crystals  when  pure,  a  yellowish  tint  indicating 
the  presence  of  free  iodine.  They  are  very  soluble  in  water,  less  so  in  alco- 
hol, and  are  always  prescribed  in  watery  solutions,  and  often  along  with 
carbonates  of  soda  or  potash,  in  order  to  prevent  decomposition  as  far  as 
possible.  The  iodide  of  potash  is  the  one  most  frequently  used  and  is  less 
liable  to  contain  free  iodine  than  the  others,  but  iodide  of  soda  is  preferred 
by  some  ;  the  dose  often  has  to  be  much  increased  beyond  that  given  above. 
The  iodide  of  ammonium  is  said  to  be  more  liable  to  cause  skin  eruptions 
and  disturbance  of  the  digestion  than  the  others.  Some  iodide  effects  may 
also  be  obtained  by  the  use  of  iodide  of  lead  or  mercury,  but  here  they 
are  complicated  by  the  action  of  the  metal,  and  these  will  be  discussed 
along  with  the  other  salts  of  lead  and  mercury.  The  external  application 
of  iodides,  as  in  the  ointment  or  liniment  of  potassic  iodide,  is  not  attended 
by  any  effect  local  or  general. 

Therapeutic  Uses.  -«—  The  iodides  are  used  very  extensively  in  the 
treatment  of  tertiary  syphilis,  in  which  they  have  proved  invaluable. 
They  have  also  been  administered  in  the  earlier  stages  of  the  disease, 
but  have  proved  to  be  of  little  service  here.  In  syphilitic  bone  disease 


IODIDES.  511 

and  ulcers,  and  in  the  gummata  of  the  brain  and  other  internal  organs, 
however,  a  remarkable  improvement  very  often  occurs  after  the  iodide 
treatment  has  been  adopted.  The  iodide  of  potassium  or  of  sodium  is 
almost  invariably  used,  and  is  given  in  as  large  doses  as  the  patient  can 
bear,  often  up  to  5  G.  (75  grs.)  daily.  In  the  beginning  of  the  tertiary 
manifestations,  the  iodide  is  often  prescribed  along  with  mercury,  and 
this  combination  is  found  more  efficient  than  the  iodide  alone.  No 
explanation  of  the  action  of  the  iodides  in  syphilis  has  been  given, 
although  it  is  surmised  that  they  may  act  as  a  specific  poison  (anti- 
septic) to  the  unknown  cause  of  the  disease.  It  is  suggested  by  some 
writers  (Binz)  that  the  iodine  is  set  free  in  the  gumma  or  in  its  neigh- 
borhood, but  this  is  pure  speculation,  unfounded  on  any  basis  of  fact. 

In  many  diseases  which  are  not  directly  attributable  to  syphilis, 
but  in  which  there  is  a  history  of  syphilis,  iodides  are  of  value ;  thus, 
neuralgia  and  other  nervous  disturbances  are  often  relieved  by  them 
in  persons  of  a  syphilitic  taint,  and  in  fact,  improvement  is  often  ob- 
served in  the  most  diverse  conditions  in  persons  who  have  formerly 
suffered  from  this  complaint. 

Another  series  of  symptoms  or  of  diseases  which  is  often  treated 
with  iodides,  is  rheumatism  in  its  various  manifestations.  The  treat- 
ment is  of  little  value  in  acute  rheumatism,  and  in  fact,  often  fails  in 
the  chronic  disease,  but  is  occasionally  attended  with  improvement, 
although  the  exact  conditions  in  which  this  occurs  are  still  unknown. 

The  iodides  have  long  enjoyed  some  reputation  in  the  treatment  of 
goitre,  but  the  thyroid  extract  has  proved  much  superior  to  them  and 
promises  to  supplant  them  entirely,  as  their  effects  are  due  to  their 
action  on  the  thyroid  secretion.  The  same  may  be  said  regarding  their 
use  in  obesity,  which  was  found  to  be  successful  in  some  cases,  pre- 
sumably of  thyroid  insufficiency.  In  normal  persons  and  animals  it 
is  often  found  that  iodides  rather  tend  to  increase  than  to  decrease  the 
weight. 

Some  skin  eruptions  have  been  found  to  be  benefited  by  the  iodide 
treatment  even  when  no  suspicion  of  syphilis  could  be  entertained. 
(Compare  thyroid  extract.) 

The  success  attending  the  treatment  of  goitre  with  iodides  seems  to 
have  been  the  basis  of  their  use  in  cases  of  enlarged  lymphatic  glands, 
scrofula,  and  lupus,  but  here  the  results  are  very  doubtful,  although 
some  authorities  allege  that  the  iodide  treatment  is  of  value.  There  is 
a  general  consensus  of  opinion  that  the  old  treatment  of  malignant 
tumors,  such  as  cancer  and  sarcoma,  with  iodides  is  hopeless. 

These  salts  are  sometimes  credited  with  promoting  the  absorption  of 
serous  effusions,  but  here  again  it  seems  doubtful  if  their  reputation  is 
merited.  The  same  may  be  said  of  their  use  to  aid  in  the  removal  of 
hypertrophy  of  connective  tissue  in  the  body,  as  in  the  various  forms 
of  sclerosis  and  cirrhosis,  although  the  iodides  are  still  very  widely 
used  in  arteriosclerosis.  Their  effect  in  removing  the  syphilitic 
gumma  was  evidently  the  origin  of  their  use  here,  but  while  the  resolu- 
tion of  gummata  under  the  iodides  is  beyond  question,  the  evidence  of 


512  INORGANIC  SALTS,   ACIDS  AND  BASES. 

improvement  in  arteriosclerosis  in  patients  free  from  syphilitic  taint  is 
not  so  decided,  and  in  fact  the  use  of  iodides  in  this  condition  is  con- 
demned by  many  authorities.  Iodide  treatment  has  no  eifect  on  the 
heart,  pulse,  or  blood-pressure  in  arteriosclerosis  even  after  prolonged 
use.  Heinz  has  attempted  to  find  a  scientific  basis  for  the  treatment 
of  exudates  and  connective  tissue  hypertrophy  with  iodides,  and  sug- 
gests that  the  vessel  walls  are  rendered  more  permeable  and  the  leuco- 
cytes more  active  by  these  salts,  but  fails  to  bring  any  convincing  evi- 
dence for  either  hypothesis. 

At  one  time  aneurism  was  treated  with  large  doses  of  iodide,  and 
improvement  was  undoubtedly  observed  in  some  cases,  in  which  there 
was  probably  a  syphilitic  taint ;  but  there  seems  no  reason  to  suppose 
that  the  iodides  have  any  special  action  on  the  vessels  apart  from  their 
antisyphilitic  action. 

Iodides  are  often  prescribed  along  with  other  remedies  in  expecto- 
rant mixtures,  the  object  being  to  render  the  bronchial  mucus  more 
watery  and  less  tenacious,  and  thus  to  facilitate  its  removal.  In  some 
cases  of  asthma  they  have  been  found  of  value,  perhaps  from  the 
same  action. 

Iodide  of  potassium  is  generally  prescribed  in  chronic  poisoning  from 
lead  or  mercury,  and  is  believed  to  hasten  the  elimination  of  these 
metals,  although  it  has  not  been  shown  that  it  is  of  more  value  here 
than  other  salts  such  as  the  chlorides  and  bromides.  The  belief  in  the 
efficacy  of  the  iodides  in  mercury  poisoning  has  suggested  that  they 
act  in  tertiary  syphilis  only  by  aiding  in  the  elimination  of  the  mer- 
cury stored  in  the  tissues  from  the  treatment  of  the  earlier  stages,  but 
this  is  incorrect,  for  the  iodides  are  of  value  in  cases  of  tertiary  syphi- 
lis in  which  mercury  has  not  been  previously  used. 

Finally,  iodide  of  potassium  is  sometimes  added  to  other  drugs  in 
cases  of  malingering,  or  in  which  it  is  suspected  that  the  patient  is  not 
taking  the  remedy  as  directed.  If  the  iodide  is  swallowed  it  can  be 
detected  in  the  urine  by  the  addition  of  a  few  drops  of  chlorine  water 
and  of  starch  solution,  which  assumes  the  well-known  blue  color. 

Iodides  have  to  be  used  with  care  in  cases  of  pulmonary  phthisis, 
in  which  they  often  increase  the  cough  and  expectoration,  and  in  some 
cases,  it  is  alleged,  cause  haemoptysis.  Children  have  sometimes  been 
found  to  suffer  with  iodism  from  being  nursed  by  a  person  under 
iodide  treatment. 

Iodism  very  often  proves  a  disagreeable  accompaniment  of  the 
treatment,  and  is  sometimes  so  severe  as  to  preclude  the  use  of  the 
salts,  so  that  many  attempts  have  been  made  to  discover  some  expedi- 
ent by  which  these  symptoms  may  be  avoided.  Most  of  these  were 
based  on  the  view  that  iodism  arises  from  the  action  of  nitrites  in  an 
acid  medium,  but  doubt  may  be  entertained  as  to  the  validity  of  this 
hypothesis,  and  there  can  be  little  question  of  the  inefficiency  of  sul- 
fanilic  acid  and  alkali  carbonate  treatment  in  cases  of  iodism.  There 
has  been  a  tendency  recently  to  ascribe  the  symptoms  to  the  tissues 
being  flooded  with  large  quantities  of  iodide,  which  are  necessary  on 


IODIDES.  513 

account  of  the  rapid  excretion,  and  more  slowly  absorbed  preparations 
have  been  suggested,  such  as  the  combination  with  fats  (lodipin,  p. 
516) ;  the  absorption  of  iodide  of  potassium  may  be  retarded  somewhat 
and  its  action  prolonged  by  prescribing  it  in  mucilaginous  fluids. 

The  cutaneous  eruptions  are  said  to  be  less  liable  to  occur  when  the 
skin  is  kept  scrupulously  clean  by  frequent  bathing. 

BIBLIOGRAPHY. 

Blum.     Munch,  med.  Woch.,  1898,  pp.  231  and  267. 

Binz.  Virchow's  Arch.,  IxiL,  p.  124.  Arch.  f.  exp.  Path,  u,  Pharm..  viii.,  p.  320 ; 
xiii.,  p.  139 ;  xxxiv.,  p.  185. 

Boehm  u.  Berg.     Arch.  f.  exp.  Path.  u.  Pharm.,  v.,  p.  329. 

Hogyes.     Ibid.,  x.,  p.  250. 

Adamkiewicz.     Char.  Annal.,  iii.,  p.  381. 

Singer.     Ztschr.  f.  klin.  Med.,  Iii.,  p.  521. 

Lesser.     Deutsch.  med.  Woch.,  1903,  No.  46. 

Ehrlich.     Char.  Annal.,  x.,  p.  129. 

Groenouw.     Therap.  Monatsh.,  1890,  p.  105. 

Rohmannu.  Malachowski.     Therap.  Monats.,  1889,  p.  301. 

Kulz.     Zeitschr.  f.  Biologic,  N.  F.,  v.,  p.  460. 

Nencki  u.  Schoumow-Simanowski.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv.,  p.  313. 

Ehlers.     Monatsh.  f.  pract.  Dermatol.,  1889,  i.,  p.  428. 

Prevost  u.  Binet.     Therap.  Monatsh.,  1890,  p.  640. 

Howald.     Zts.  f.  physiolog.  Chem.,  xxiii.,  p.  209. 

Annuschat.     Arch.  f.  exp.  Path.  u.  Pharm.,  x.,  p.  261. 

Anten.     Arch.  f.  exp.  Path  u.  Pharm.,  xlviii.,  p  331. 

Stockman  and  Charteris.  Journ.  of  Physiol.,  xxvi.,  p.  277 ;  Brit.  Med.  Journ.,  Nov. 
23,  1901. 

Heinz.     Virchow's  Arch.,  civ.,  p.  44. 

Gumprecht.     Verhandl.  d.  Congress,  f.  inn.  Med.,  xix.,  p.  260. 

VI.    IODINE. 

Iodine  possesses  a  local  irritant  action  similar  to,  though  less  intense 
than  that  of  chlorine  and  bromine.  It  is  much  less  volatile,  and  there- 
fore comes  into  contact  with  the  tissues  more  slowly  than  these,  but 
the  chemical  change  is  analogous,  and  iodides  and  proteid  compounds 
result.1 

Action.  —  When  applied  to  the  Skin,  it  dyes  it  a  yellow-brown  or 
dark  brown  color,  and  acts  as  an  irritant,  producing  a  sensation  of  heat 
and  itching.  In  very  concentrated  solution  or  in  the  solid  form,  it 
may  cause  blistering  or  even  corrosion,  but  it  acts  much  more  slowly 
than  most  other  irritants,  and  at  the  same  time  the  irritation  is  more 
prolonged.  It  penetrates  into  the  deeper  layers  of  the  skin,  and  small 
quantities  are  absorbed. 

The  Mucous  Membranes  are  more  strongly  affected  by  contact  with 
it ;  thus  when  its  vapor  is  inhaled  for  some  time,  smarting,  swelling 
and  increased  secretion  is  caused  in  the  nasal  mucous  membrane, 
conjunctiva,  throat  and  lower  respiratory  passages,  resembling  exactly 
the  symptoms  known  as  iodism.  In  the  stomach  small  quantities  may 

1  It  therefore  differs  entirely  from  the  iodides  and  the  other  salts,  as  far  as  its  local 
action  is  concerned,  but  there  are  so  many  points  of  connection  between  the  halogen 
and  the  salts  that  it  has  been  found  convenient  to  insert  it  here.     The  same  remark 
holds  good  for  the  next  series  (lodoform). 
33 


514  INORGANIC  SALTS,    ACIDS  AND  BASES. 

cause  slight  irritation  and  improved  appetite,  but  as  a  general  rule 
nausea,  discomfort  and  vomiting  follow  its  administration  in  any  save 
the  most  minute  doses,  and  occasionally  diarrhrea  has  been  observed 
after  it  from  irritation  of  the  bowel.  In  cases  of  poisoning,  the  irri- 
tation of  the  alimentary  canal  may  prove  fatal  by  inducing  collapse 
and  failure  of  the  heart  and  respiration,  and  iodine  may  be  recognized 
in  the  vomited  matter  and  in  the  stools. 

Solutions  of  iodine  Injected  Subcutaneously  or  into  tumors  or  cysts, 
a  common  method  of  treatment  formerly,  cause  intense  pain  and  irri- 
tation which  may  induce  collapse  and  which  have  been  followed  in 
some  instances  by  suppuration  and  gangrene. 

Iodine  is  Absorbed  in  the  form  of  iodides,  and  perhaps  in  a  combi- 
nation with  proteids.  The  ordinary  iodalbuminate  obtained  by  adding 
iodine  to  albumin,  is  a  very  loose  compound,  and  is  easily  decomposed 
by  dialysis,  or  by  heating  it  to  the  coagulation  point  of  the  albumin, 
when  the  iodine  is  obtained  free  or  in  combination  with  alkalies.  Sev- 
eral stronger  and  more  definite  compounds  have  been  formed  recently, 
and  it  is  not  impossible  that  the  iodalbuminate  formed  in  the  process 
of  absorption  is  of  a  similar  nature.  In  combination  with  albumin, 
iodine  fails  to  give  the  starch  reaction.  Its  Fate  in  the  Body  is  pre- 
cisely similar  to  that  of  the  iodides  —  it  is  excreted  in  the  form  of 
iodides,  chiefly  by  the  kidneys,  to  a  less  extent  in  the  saliva,  perspira- 
tion, milk,  and  secretions  of  the  respiratory  passages.  It  also  occurs 
in  the  stomach,  into  which  it  appears  to  be  excreted  as  hydriodic 
acid ;  free  iodine  has  been  detected  here  in  both  man  and  animals, 
and  is  probably  formed  by  the  decomposition  of  the  acid.  In  the 
normal  organism  iodine  is  contained  in  considerable  quantity  in  the 
thyroid  gland  in  the  form  of  an  organic  compound,  iodothyrin,  and  in 
many  cases  the  administration  of  iodine  leads  to  an  increase  in  the  for- 
mation of  this  substance,  perhaps  by  actually  stimulating  the  secretory 
cells  of  the  thyroid,  but  more  probably  by  affording  them  a  larger 
amount  of  a  necessary  constituent  of  their  secretion  than  is  contained 
in  ordinary  food. 

Small  quantities  of  iodine  may  be  given  internally  to  many  persons 
without  eliciting  any  symptoms  except  those  which  are  clearly  due  to 
the  local  action.  Repeated  doses,  however,  sometimes  cause  symp- 
toms resembling  those  observed  after  iodides  (lodism),  although  these 
have  been  much  less  often  induced  by  iodine,  which  is  comparatively 
seldom  administered  internally.  Skin  affections  seem  to  be  extremely 
rare,  but  that  a  similar  action  on  the  skin  may  be  induced  by  iodine 
and  iodides,  is  shown  by  the  application  of  iodine  to  the  skin  being 
often  followed  by  eruptions,  which  are  not  confined  to  the  point  of 
application  but  spread  over  the  skin  and  assume  the  form  of  diffuse 
erysipelatoid  rashes,  papules,  or  erythemata.  Fever  is  said  to  occur 
occasionally,  especially  in  goitrous  patients,  and  a  loss  of  flesh  has  been 
observed  with  shrinking  in  size  of  the  thyroid  gland  and,  it  is  said,  of 
the  mammae  and  testicles.  The  puke  is  often  accelerated  to  a  very 
considerable  extent,  and  in  cases  of  goitre  treated  for  some  time  by  the 


IODINE.  515 

internal  and  local  administration  of  iodine,  a  curious  nervous  condition 
was  often  observed  formerly.  The  patients  became  restless,  anxious 
and  irritable,  and  suffered  from  sleeplessness  and  often  from  tremor, 
which  sometimes  simulated  chorea.  All  of  these  symptoms  except  the 
skin  eruptions  and  the  atrophy  of  the  mamma  and  testis,  the  occurrence 
of  which  under  iodine  requires  confirmation,  are  induced  by  large  quanti- 
ties of  thyroid  extract  also,  and  would  seem  to  be  due  to  the  excessive 
production  of  iodothyrin. 

Irritation  of  the  respiratory  tract  is  seen  less  often  after  iodine  than 
after  the  iodides,  but  oedema  of  the  larynx  has  been  observed,  and  in 
rare  cases  cough  and  the  expectoration  of  a  watery  secretion  tinged 
with  blood. 

Anuria  and  albuminuria  have  occurred  in  a  few  instances. 

The  symptoms  induced  by  iodine  after  absorption  thus  resemble  in 
general  features  those  following  the  use  of  the  iodides,  but  while  the 
latter  tend  to  cause  irritation  of  the  skin  and  respiratory  tract,  pre- 
sumably through  liberating  iodine  here,  the  chief  effects  of  iodine  after 
absorption  are  due  to  its  action  on  the  thyroid  gland,  the  effects  on  the 
skin  and  mucous  membranes  being  less  prominent. 

The  effects  of  iodine  on  the  Metabolism  are  still  a  matter  of  dispute, 
some  authors  finding  no  alteration,  while  others  state  that  the  excretion 
of  urea  is  increased.  They  probably  differ  in  different  individuals 
according  to  the  condition  of  the  thyroid  gland. 

Injected  into  the  veins  of  animals,  iodine  causes  oedema  of  the  lungs, 
which  v.  Zeissl  considers  to  be  due  in  part  to  changes  in  the  left  ven- 
tricle, in  part  to  contraction  of  the  pulmonary  arterioles. 

The  muscles  of  the  frog  are  thrown  into  a  state  of  rigor  by  iodine  in 
the  same  way  as  by  the  iodides. 

Some  Cases  of  Poisoning  from  the  injection  of  large  quantities  of 
iodine  into  cysts  have  been  recorded.  In  Rose's  well-known  case,  the 
chief  symptoms  were  thirst,  constant  vomiting,  the  vomited  matter 
containing  iodine,  cyanosis  and  coldness  of  the  skin,  a  small,  weak 
pulse,  anuria  and  skin  eruptions  after  a  few  days ;  and  death  occurred 
on  the  tenth  day.  In  such  cases  of  poisoning  in  man  the  mucous 
membrane  of  the  stomach  and  intestine  has  been  found  swollen  and 
loosened,  and  in  animals  fatty  degeneration  of  the  liver,  heart  and 
kidney  has  been  described. 

Iodine  is  said  to  dissolve  the  red  blood  corpuscles  when  it  is  brought 
in  contact  with  them  outside  the  body,  and  to  form  a  combination  with 
hemoglobin. 

PREPARATIONS. 

lodum  (U.  S.  P.,  B.  P.),  iodine,  a  heavy,  friable,  bluish-black  mass,  with 
a  characteristic  odor  and  acrid  taste,  insoluble  in  water,  soluble  in  alcohol 
and  in  solutions  of  the  iodides  of  the  alkalies.  Iodine  itself  is  not  used  in 
therapeutics.  The  solutions  are  of  a  brown  color. 

Tinctura  lodi  (U.  S.  P.),  7  per  cent.,  0.1-0.4  c.c.  (2-8  mins.). 

Tinctura  lodi  (B.  P.),  2£  per  cent.,  2-5  mins. 

Liquor  lodi  Compositus  (U.  S.  P.),  Lugol's  Solution,  contains  5  per  cent, 
dissolved  in  10  per  cent,  potassium  iodide  solution.  0.2-0.8  c.c.  (3-12  mins.). 


516  INORGANIC  SALTS,   ACIDS  AND  BASES. 

Unguentum  lodi  (U.  S.  P.,  B.  P.),  4  per  cent 

Liquor-  lodi  Fortis  (B.  P.),  Iodine  Liniment,  about  14  per  cent. 

Sulphuris  lodidum  (U.  S.  P.,  B.  P.)  is  a  mixture  of  iodine  and  sulphur, 
part  of  which  may  be  in  chemical  combination.  It  resembles  iodine  in  its 
action  on  the  skin. 

Unguentum  Sulphuris  lodidi  (K  P.). 

The  compound  solution  of  iodine  is  the  preparation  best  fitted  for  internal 
use,  although  the  tincture  is  also  employed.  Both  should  be  given  after 
meals  and  as  far  as  possible  diluted  with  demulcent  preparations,  in  order 
to  avoid  irritation  of  the  stomach. 

For  injection  into  cysts  or  tumors  the  compound  liquid  is  also  the  best 
preparation,  as  it  is  less  irritant  than  the  tincture. 

The  tincture,  ointment,  the  strong  solution  (B.  P.)  and  the  sulphur  iodide 
preparation  may  be  used  for  external  application. 

Therapeutic  Uses.  —  Iodine  has  been  used  internally  in  a  variety  of 
chronic  conditions  such  as  syphilis  and  goitre,  and  in  tubercular  dis- 
ease of  the  glands,  bones  and  other  organs,  but  it  has  been  almost 
entirely  superseded  by  the  iodides,  and  in  goitre  by  the  thyroid  prepara- 
tions. It  was  formerly  applied  in  goitre  by  injection  into  the  enlarged 
lobes  of  the  gland,  as  well  as  being  administered  internally,  and  cer- 
tainly proved  beneficial  in  many  cases,  though  these  are  better  treated 
now  by  the  extracts  of  the  gland. 

The  internal  use  of  iodine  has  undergone  a  revival  quite  recently,  but  in- 
stead of  the  older  solutions,  new  preparations  have  been  introduced  such  as 
the  combinations  with  proteids  (Eigon,  lodolen)  or  with  fats  (lodipiri),  and 
the  organic  compounds  of  the  iodoform  series.  lodipin  is  decomposed  by 
the  pancreatic  juice  and  iodides  appear  in  the  urine  soon  after  this  takes 
place.  It  has  been  used  to  indicate  the  activity  of  the  gastric  movements, 
as  when  these  are  abnormally  slow  the  reaction  in  the  urine  appears  later 
than  in  normal  cases. 

Iodine  has  been  applied  locally  by  painting  on  the  skin  in  a  variety 
of  chronic  inflammatory  processes,  such  as  tubercular  glands,  pleuritic 
effusion,  and  tubercular  or  rheumatic  joint  disease.  Its  action  here 
consists  simply  of  a  mild  lasting  irritation  of  the  skin,  which  induces 
some  congestion  in  the  subcutaneous  tissues  and  may  thus  aid  in  the 
absorption  of  exudates  in  them  and  may  also  influence  the  deeper  lying 
tissues  and  organs  in  the  same  way  as  other  irritants  (see  page  78). 
There  is,  however,  nothing  specific  in  its  action,  and  it  differs  from  the 
other  skin  irritants  only  in  being  milder  in  action  and  more  enduring 
in  its  effects.  It  seems  unlikely  that  the  small  quantity  absorbed  can 
have  any  appreciable  action.  Some  benefit  often  follows  from  this 
use  of  iodine  in  chronic  inflammations,  but  there  is  no  question  that  it 
is  very  often  applied  where  more  active  surgical  measures  are  really 
required. 

Iodine  has  been  very  frequently  injected  into  cysts  in  order  to  in- 
duce inflammation  and  adhesion  of  their  walls,  and  thus  to  obliterate 
the  cavity.  Formerly  ovarian  cysts  were  very  generally  treated  in 
this  way,  but  a  number  of  cases  of  poisoning  arising  from  this  treat- 
ment, and  the  progress  of  abdominal  surgery  have  led  to  its  being 
abandoned.  Hydrocele  is  still  very  frequently  treated  with  iodine  in- 


IODOFORM.  517 

jection,  and  some  cysts  of  the  membranes  of  the  spinal  cord  and  brain 
are  injected  with  it.  It  has  been  stated  in  this  connection  that  these 
membranes  react  much  less  violently  to  iodine  than  the  peritoneum 
and  the  lining  membranes  of  the  joints.  Iodine  has  also  been  injected 
in  dilute  solution  into  the  pleuritic  cavity  after  the  evacuation  of 
empyema. 

BIBLIOGRAPHY. 

See  Iodides,  Thyroid  Extract. 

Liebrecht.     Centralbl.  f.  Physiol.,  1897,  p.  835. 

Hofmeister.     Ztschr.  f.  phys.  Chem.,  xxiv.,  p.  159. 

Winternitz.     Ibid.,  xxiv.,  p.  425. 

Levene.     Amer.  Journ.  of  Phys.,  ii.,  p.  15. 

VII.     IODOFORM. 

A  number  of  iodine  compounds  have  been  introduced  into  thera- 
peutics as  applications  to  wounded  surfaces.  The  most  widely  known 
of  these  is  lodoform  (CHI3),  which  corresponds  in  its  chemical  struc- 
ture to  chloroform,  and  forms  a  yellow,  crystalline,  insoluble  powder 
with  an  intensely  disagreeable  odor.  It  has  been  used  very  exten- 
sively in  surgery,  and  has  given  rise  to  poisoning  in  a  number  of  cases. 

Symptoms.  —  The  symptoms  of  iodoform  intoxication  in  man  gener- 
ally set  in  with  anxiety,  general  depression  and  discomfort.  The  pa- 
tient becomes  sleepless  and  restless,  complains  of  giddiness  and  head- 
ache and  often  of  the  taste  and  odor  of  iodoform  in  the  mouth  and 
nose.  The  pulse  is  generally  greatly  accelerated,  and  a  rise  of  tem- 
perature is  said  to  have  occurred  in  some  cases  in  which  no  septic 
poisoning  could  be  found  to  account  for  it.  The  depression  deepens 
into  true  melancholia  accompanied  by  hallucinations,  the  patient  often 
suffering  from  the  illusion  of  persecution,  which  may  induce  him  to 
attempt  suicide.  As  a  general  rule  this  melancholia  is  followed  by 
attacks  of  violent  delirium  and  mania,  lasting  for  hours  or  days,  and 
in  fatal  cases,  by  collapse  and  death.  In  other  cases  the  condition  has 
passed  into  permanent  insanity  and  dementia.  A  rarer  result  of  the 
absorption  of  iodoform  is  deep  sleep  passing  into  stupor  and  collapse 
without  any  symptoms  of  cerebral  excitement. 

In  milder  cases  of  poisoning  the  patient  suffers  only  from  the  un- 
pleasant taste  and  odor,  from  headache  and  not  infrequently  from 
nausea  and  vomiting. 

In  the  dog  and  cat  iodoform  generally  causes  deep  sleep  and  stupor, 
with  lessened  excitability  of  the  spinal  cord  and  of  the  motor  areas  of 
the  brain.  In  the  frog  it  paralyzes  the  central  nervous  system  and  the 
heart  without  eliciting  any  symptoms  of  excitement.  No  narcosis  is 
observed  in  the  rabbit  even  after  fatal  doses. 

The  symptoms  most  characteristic  of  iodoform  poisoning  —  those  of 
delirium  and  mania  —  are  evidently  due  to  cerebral  disturbance,  but 
nothing  is  known  as  to  the  nature  of  the  changes  in  the  brain.  No 
other  poison  elicits  these  symptoms  in  the  same  intensity  and  of  equal 
duration,  and  no  similar  effects  have  been  met  with  in  animals. 


518  INORGANIC  SALTS,   ACIDS  AND  BASES. 

Acceleration  of  the  heart  has  been  noted  in  many  cases  of  poisoning. 
After  prolonged  administration  albuminuria  is  often  observed  in  ani- 
mals, and  the  thyroid  secretion  has  been  found  to  be  increased  to  a 
very  considerable  extent  by  iodoform,  as  by  other  bodies  which  free 
iodine  in  the  tissues. 

After  fatal  iodoform  poisoning  in  man  and  animals,  the  liver,  kidney, 
heart  and  muscles  are  generally  found  to  have  undergone  fatty  degen- 
eration. In  addition,  irritation  of  the  gastric  and  intestinal  mucous 
membrane  has  been  observed,  and  the  epithelial  cells  are  often  degen- 
erated. Ecchymoses  occur  beneath  the  endocardium,  in  the  kidney 
and  elsewhere,  and  congestion  of  the  meninges  is  described. 

Absorption  and  Excretion.  —  Iodoform  is  readily  decomposed  in  the 
presence  of  alkaline  fluids  and  in  proteid  solutions,  and  some  decom- 
position undoubtedly  takes  place  in  wounds ;  the  iodine  liberated 
combines  with  the  alkalies  of  the  fluids  to  form  iodides,  for  these  have 
been  shown  to  be  present,  and  iodalbuminates  are  presumably  formed  in 
the  same  way  as  by  free  iodine.  Some  of  the  iodoform,  however,  is 
absorbed  unchanged,  for  the  nervous  symptoms  are  not  produced  by 
iodine  or  iodides.  After  iodoform  absorption,  iodine  has  been  shown 
to  be  present  in  the  saliva,  perspiration  and  bronchial  secretion,  as 
after  the  ingestion  of  iodine  or  iodides  ;  but  it  is  chiefly  excreted  in 
the  urine  in  the  form  of  iodides.  The  tissues  apparently  retain  it  very 
tenaciously,  for  iodides  have  been  found  in  the  urine  for  more  than  a 
month  after  the  administration  of  iodoform. 

In  considering  the  symptoms  of  iodoform  intoxication,  it  must  be 
recognized,  therefore,  that  a  very  complex  condition  is  present.  Some 
iodoform  circulates  in  the  blood  apparently  unchanged  and  gives  rise 
to  the  cerebral  symptoms.  Other  symptoms  are  due  to  the  presence 
of  iodine  and  iodides,  perhaps  the  former  chiefly,  in  the  blood  and  tis- 
sues, for  Rummo  observed  in  dogs  the  excessive  secretion  from  the 
eyes,  nose  and  bronchi,  which  is  characteristic  of  iodism.  Lastly, 
the  acceleration  of  the  heart  and  some  other  symptoms  may  be  due  to 
abnormal  activity  of  the  thyroid  secretory  cells. 

Poisoning  with  iodoform  is  much  more  liable  to  occur  in  adults  than 
in  children.  Serious  symptoms,  especially  mental  symptoms,  are  often 
developed  only  after  somewhat  prolonged  administration,  but  in  renal 
disease  the  iodoform  products  are  excreted^more  slowly  than  usual,  and 
are  liable  to  accumulate  in  the  tissues,  so  that  it  is  to  be  used  with 
caution. 

Iodoform  has  no  marked  Local  Action  on  the  skin  or  mucous  mem- 
branes. When  applied  to  wounded  surfaces  it  sometimes  causes  some 
irritation  in  the  neighborhood  and  even  exanthemata,  but  these  are  rare, 
and  appear  to  occur  only  in  persons  predisposed  to  cutaneous  disease. 
It  seems  to  have  some  ansesthetic  action,  when  applied  in  large  quantity 
to  wounded  surfaces.  Iodoform  was  at  first  applied  to  wounds  in  the 
belief  that  its  Antiseptic  properties  were  equal  to  or  even  exceeded 
those  of  carbolic  acid.  It  has  been  shown,  however,  that  it  possesses 
little  or  no  influence  on  the  cultures  of  most  of  the  pathogenic  mi- 


IODOFORM.  519 

crobes,  for  the  spores  often  develop  as  rapidly  after  having  been  sub- 
jected to  iodoform  as  in  the  control  cultures.  It  has  therefore  been 
suggested  that  while  iodoform  in  itself  possesses  no  antiseptic  virtues, 
the  iodine  formed  from  it  in  the  wound  ma}7  retard  the  growth  of  sep- 
tic germs.  And  in  regard  to  this  point  bacteriologists  are  not  agreed, 
for  while  several  investigations  tend  to  show  that  microbes  drawn  from 
wounds  under  iodoform  treatment  are  not  retarded  or  weakened  in  their 
development,  other  experiments  indicate  that  the  virulence  of  some 
germs  is  reduced.  Some  of  the  advocates  of  the  iodoform  treatment 
therefore  ascribe  its  results  to  this  slight  antiseptic  action  of  the  iodine, 
while  others  suppose  that  it  diminishes  the  secretion  of  the  wounded 
surface  and  thus  aifords  a  less  suitable  medium  for  the  growth  of  the 
germs ;  in  this  relation  it  may  be  mentioned  that  Binz  found  the  emi- 
gration of  the  leucocytes  from  the  blood  vessels  hindered  by  the  local 
application  of  iodoform.  Finally  iodoform  may  retard  the  growth  of 
microbes  to  some  extent  by  forming  a  crust  over  the  wounded  surface, 
and  mechanically  preventing  them  from  penetrating  to  it. 

The  intensely  disagreeable  odor  of  iodoform  and  the  considerable 
number  of  cases  of  poisoning  noted  under  its  use  have  led  to  the  intro- 
duction of  numerous  substitutes  in  the  last  ten  years.  Some  of  these 
have  been  shown  to  be  practically  worthless  and  have  been  discarded, 
while  the  greater  number  are  apparently  used  more  or  less  widely,  but 
accurate  data  as  to  their  value  cannot  be  obtained.  None  of  them  seem 
to  be  very  poisonous,  and  in  most  of  them  the  iodine  of  the  molecule 
is  not  liberated  in  the  wound  or  tissues.  It  is  of  course  impossible  to 
state  how  far  they  are  capable  of  replacing  iodoform,  as  long  as  their 
exact  action  in  wounds  is  unknown. 

The  first  of  these  substitutes  was  iodol  or  tetraiodpyrrol  (C4I4NH),  which 
has  no  odor  or  taste,  is  insoluble  in  water,  but  is  absorbed  from  mucous  sur- 
faces and  from  wounds.  It  is  decomposed  in  the  tissues,  and  leads  to  the 
excretion  of  iodides  in  the  urine,  and  in  very  large  doses  gives  rise  to  symp- 
toms in  animals  resembling  those  produced  by  iodoform.  The  iodine  of 
iodol  is  apparently  less  easily  split  off  the  molecule  than  that  of  iodoform, 
and  it  seems  on  the  whole  less  liable  to  produce  poisoning,  but  has  been  less 
used  of  late  years  than  some  of  its  rivals.  Among  the  best  known  of  these 
are  aristol  or  dithymol-diiodide  (C6H2CH3C3H7OI)2,  and  the  sozoiodolates  of 
potassium,  sodium,  mercury  and  zinc.  Sozoiodolic  acid  is  phenol-sulphonic 
acid  in  which  two  atoms  of  hydrogen  have  been  substituted  by  two  atoms  of 
iodine  (C6H2I2HOSO2OH).  Iodine  compounds  of  phenol-phthalein  are  known 
by  the  trade  names  of  nosophen,  antinosine  and  eudoxine.  Triiodocresol  is 
known  as  losophan,  while  europhen  is  a  more  complex  combination  of  cresol 
and  iodine ;  loretin  and  vioform  are  derivatives  of  quinoline  containing 
iodine.  (See  also  under  Bismuth  and  Alum.)  These  later  u  substitutes  "  for 
iodoform  differ  entirely  from  it  and  from  iodol  in  the  fact  that  iodine  is  not 
liberated  by  the  tissues  ;  that  they  pass  through  the  body  unchanged,  as  far 
as  the  iodine  is  concerned,  and  that  they  are  said  to  be  entirely  devoid  of 
poisonous  effects,  and  in  fact  of  any  action,  save  as  local  antiseptics.  Their 
value  as  antiseptics  can  only  be  determined  by  further  trial.  They  are 
almost  all  phenol  derivatives,  and  any  virtues  they  possess  may  prove  to  be 
due  to  this  fact  mainly,  and  not  to  their  containing  iodine. 


520  INORGANIC  SALTS,  ACIDS  AND  BASES. 

PREPARATIONS. 

lodoformum  (U.  S.  P.,  B.  P.),  iodoform  (CHI3),  forms  small,  lemon-colored 
crystals,  possessing  a  very  penetrating,  persistent  and  disagreeable  odor  and 
taste,  practically  insoluble  in  water,  soluble  in  alcohol,  ether,  fixed  oils, 
glycerin,  etc.  0.03-0.2  G.  Q-3  grs.),  in  pills  or  capsules. 

Suppositoria  lodoformi  (B.  P.),  each  containing  3  grs.  of  iodoform. 

UNGUENTUM  IODOFORMI  (U.  S.  P.,  B.  P.),  contains  10  per  cent,  iodoform. 

lodolum  (U.  S.  P.),  C4I4'NH,  a  light  grayish-brown  crystalline  powder,  taste- 
less, odorless,  insoluble  in  water.  Dose,  0.25  G.  (4  grs.). 

Thijmolis  lodidum  (U.  S.  P.),  Aristol  ((C6H2-  CH3-  C3H7-  OI)2)  a  yellowish- 
brown  powder  resembling  iodol  in  its  properties. 

The  Sozoiodolate  of  potassium  is  slightly  soluble  in  water,  the  sodium  and  zinc 
salts  more  soluble.  Mercury  forms  an  insoluble  salt  which  may  be  dissolved  by 
the  addition  of  sodium  chloride. 

Therapeutic  Uses.  —  Iodoform  has  been  used  to  a  very  limited  extent 
internally  in  the  treatment  of  syphilis,  and  as  an  intestinal  disinfectant. 
It  is  chiefly  employed  in  surgical  treatment  as  an  application  to  wounds, 
skin  diseases  and  burns.  In  granulating  surfaces  with  a  profuse  secre- 
tion, and  in  slowly  healing  abscess  cavities,  it  seems  to  be  especially 
valuable.  It  may  be  applied  as  a  dusting  powder,  as  an  ointment,  or 
in  gauze  or  bandages  saturated  with  it.  It  has  been  shown  that  it 
has  very  weak  antiseptic  properties,  and  many  surgeons  take  the 
precaution  of  disinfecting  the  powder  before  applying  it,  and  use  it 
for  its  effect  on  the  tissues  of  the  wound  and  not  for  its  effects  on  the 
germs.  Applied  in  ordinary  quantity  to  small  surfaces  it  seems  to 
be  a  perfectly  safe  remedy,  cases  of  poisoning  occurring  only  when 
large  cavities  are  plugged  with  it,  or  when  it  is  applied  to  very  large 
absorbent  surfaces.  Many  attempts  have  been  made  to  disguise  its 
disagreeable  odor,  but  have  been  attended  with  only  moderate  success. 
Among  the  best  of  the  many  perfumes  suggested  for  this  purpose  is 
cumarin,  which  is  contained  in  large  quantity  in  the  Tonka  bean. 

Iodoform  has  been  credited  with  some  specific  action  in  tubercular 
disease,  but  has  proved  almost  inert  towards  the  bacillus.  The  favor- 
able results  in  the  local  treatment  of  tubercular  abscesses,  laryngeal 
ulcers  and  similar  conditions  may  with  greater  probability  be  attributed 
to  its  action  on  the  granulation  tissue.  In  syphilitic  ulcers  and  chan- 
cres, iodoform  has  been  used  very  largely  and  with  good  effects. 

Iodol  may  be  used  as  a  substitute  for  iodoform,  and  is  applied  in 
the  same  way.  The  sozoiodolates  are  used  as  powders  or  ointments, 
or  in  the  case  of  the  sodium,  zinc,  and  mercury  salts,  in  solution.  The 
last  is  poisonous,  and  is  comparable  to  corrosive  sublimate  in  its  effects. 

BIBLIOGRAPHY. 

Rummo.     Arch,  de  Phys.,  norm,  et  path.,  1883,  ii.,  p.  145. 

Binz.  Arch.  f.  exp.  Path.  u.  Pharm.,  viii.,  p.  G09  ;  xiii.,  p.  113.  Virchow's 
Arch.,  Ixxxix.,  p.  389. 

Behring.     Deutsch.  med.  Woch.,  1882,  p.  278. 

Zeller.     Arch.  f.  klin.  Chirurg.,  xxviii.,  p.  590.    Zts.  f.  physiol.  Chemie,  viii.,  p.  70. 

Harnack.     Berl.  klin.  Woch.,  1883,  p.  723,  and  1885,  p.  98. 

Falkson.     Arch.  f.  klin.  Chirurg.,  xxviii.,  p.  112. 

Neisser.     Virchow's  Arch.,  ex.,  p.  381. 


FLUORIDES.  521 

Baumgarten.     Berl.  klin.  Woch.,  1887,  p.  354. 

Marcus.     Berl.  klin.  Woch.,  1886,  p.  342.     (lodol.) 

Sattler.     Fortschr.  d.  Med.,  1887,  p.  362.     (lodol.) 

Lrnnry.     Arch.  f.  klin.  Chirurg.,  liii.,  p.  787. 

Meyer.     Ibid.,  lv.,  p.  676. 

Schmidt.     Arch,  internat.  de  Pharmacodyn. ,  viii.,  pp.  Ill,  187;  ix.,  p.  107. 

Altenburg.     Ibid.,  viii.,  p.  125. 

VIII.    FLUORIDES. 

The  fluorides  present  many  points  of  difference  from  the  other  halogen 
salts  in  their  chemical  reactions  and  also  in  their  effects  in  the  organism. 

The  fluoride  of  sodium,  which  alone  has  been  examined,  possesses  a  power- 
fully irritant  local  action,  which  is  seen  most  clearly  when  it  is  applied  to 
the  mucous  membranes  of  the  eye  or  of  the  alimentary  tract.  In  the  for- 
mer it  causes  congestion  and  inflammation  of  the  conjunctiva  and  opacity 
of  the  cornea,  when  it  is  applied  in  a  two  per  cent,  solution  for  some  time. 
Small  quantities  induce  irritation  of  the  stomach,  nausea  and  vomiting,  and 
the  prolonged  administration  leads  to  irritation  of  the  intestines  and  diar- 
rhoea ;  solutions  of  the  fluorides  are  absorbed  with  great  difficulty  by  the  in- 
testinal epithelium.  When  injected  subcutaneously  fluorides  often  induce 
inflammation  and  suppuration  with  necrosis. 

In  frogs  small  doses  induce  prolonged  fibrillary  contractions  of  the  mus- 
cles throughout  the  body,  which  are  due  to  a  stimulation  of  the  terminations 
of  the  motor  nerves.  Larger  doses  paralyze  the  central  nervous  system  and 
eventually  the  motor  terminations,  and  even  the  nerve  fibres.  The  muscles 
lose  their  irritability  and  pass  into  very  marked  rigor,  and  the  heart  muscle 
is  also  paralyzed  by  large  quantities. 

In  mammals  the  first  symptoms  are  increased  secretion  of  saliva  and 
tears,  acceleration  and  deepening  of  the  respiration,  followed  by  a  condition 
of  weakness  and  somnolence.  Strong  fibrillary  tremor  of  the  muscles  then 
sets  in  with  occasional  stronger  twitches,  which  eventually  pass  into  attacks 
of  general  convulsions.  In  the  intervals  between  the  convulsions  the  animal 
lies  in  a  state  of  profound  coma.  The  respiration  is  finally  arrested  during 
an  attack  of  convulsions,  the  heart  continuing  to  beat  for  some  time  longer. 

Tappeiner  found  a  very  marked  fall  of  blood-pressure  produced  by  sodium 
fluoride,  aud  attributed  it  to  depression  of  the  vaso-motor  centre.  It  may 
in  part  account  for  the  stupor,  but  this  indirect  action  is  in  all  probability 
strengthened  by  a  direct  depression  of  the  higher  nervous  centres.  The 
convulsions  are  central  in  origin,  while  the  cause  of  the  fibrillary  contrac- 
tions in  mammals  is  unknown.  The  respiratory  centre  seems  to  be  first 
stimulated  and  then  paralyzed.  Muscles,  nerves  and  other  excised  tissues 
die  much  sooner  in  solutions  of  sodium  fluoride  than  in  corresponding  ones 
of  the  chloride,  iodide  or  bromide,  so  that  the  fluoride  ion  must  be  assigned 
a  position  quite  distinct  from  the  other  halogen  ions  in  the  scale  of  toxicity. 

The  fluorides  absorbed  from  the  alimentary  canal  are  excreted  by  the 
urine,  but  this  takes  place  very  slowly,  and  much  of  the  fluoride  is  stored  up 
in  the  body,  some  in  the  liver  and  skin,  but  most  in  the  bones  in  the  form 
of  calcium  fluoride.  Crystals  of  this  very  insoluble  salt  are  found  in  masses 
in  the  Haversian  canals,  and  increase  the  hardness  and  brittleness  of  the 
bones. 

The  prolonged  administration  of  fluorides  to  animals  has  been  found  to 
cause  weakness,  loss  of  flesh,  and  irritation  and  ulceration  of  the  gums. 

The  fluoride  of  sodium  has  considerable  antiseptic  power,  putrefaction  be- 
ing delayed  by  the  addition  of  one  part  to  500  of  fluid,  and  one  in  200  ar- 
resting completely  the  growth  of  bacteria.  It  has  been  used  to  a  very  limited 
extent  as  a  surgical  antiseptic. 

Hydrofluoric  acid  is  an  exceedingly  powerful  caustic,  destroying  the 
mucous  membranes  wherever  it  comes  in  contact  with  them.  It  has  been 


522  INORGANIC  SALTS,   ACIDS  AND  BASES. 

observed  that  workers  in  certain  departments  of  glass  factories,  in  which  the 
atmosphere  contains  a  small  amount  of  this  acid,  are  very  seldom  attacked 
by  tuberculosis,  and  an  attempt  has  been  made  to  treat  pulmonary  phthisis 
by  the  inhalation  of  very  dilute  vapors.  The  results  have  not  been  success- 
ful, although  there  is  no  question  that  hydrofluoric  acid  is  a  powerful  ger- 
micide. 

Sodium  fluorosilicate  (SiFlNa2)  has  also  been  used  as  an  antiseptic  in  so- 
lution. It  has  been  found  to  cause  nausea,  eructation  and  slowness  of  the 
pulse  when  swallowed. 

BIBLIOGRAPHY. 

Tappeiner.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxv.,  p.  203;  xxvii.,  p.  108. 

Schuk.     Ibid.,  xxv.,  p.  326. 

Hewelke.     Deutsch.  med.  Woch.,  1890,  p.  477. 

Langgaard.     Therap.  Monatsh.,  1888,  p.  178. 

Gottbrecht.     Ibid.,  1889,  p.  411. 

Brandl  u.  Tappeiner.     Ztschr.  f.  Biologie,  x.,  p.  518. 

Bokenham.     Brit.  Med.  Journ.,  1890,  p.  355. 

Miiller.     Inaug.  Diss.,  Greifswald,  1889. 

Siegfried.     Arch,  internat.  de  Pharmacodyn.,  ix.,  p.  225. 

IX.    CHLORATES. 

The  chlorate  of  potassium,  introduced  into  therapeutics  on  the  erro- 
neous theory  that  it  would  supply  oxygen  to  the  tissues,  has  been  used 
very  extensively  for  its  effects  in  certain  diseases  of  the  mouth.  It 
was  supposed  to  be  entirely  devoid  of  poisonous  properties,  but  was 
shown  by  Jacobi  to  give  rise  to  very  grave  and  even  fatal  symptoms 
in  some  instances.  In  such  cases  the  symptoms  are  due  partly  to 
the  salt-action,  but  chiefly  to  the  specific  effects  of  the  chlorate  ion. 
The  chlorate  of  sodium  induces  these  chlorate  symptoms,  and  the 
chlorate  of  ammonium  is  said  to  be  the  most  poisonous  of  the  three. 
It  would  seem  that  the  conditions  which  determine  their  appearance 
are  not  universally  present,  for  very  often  large  quantities  have  been 
taken  with  impunity,  while  in  other  individuals  much  smaller  quanti- 
ties have  induced  grave  poisoning. 

Symptoms.  —  The  chlorates  have  a  cool,  saline  taste,  which  persists 
for  a  long  time  owing  to  their  being  excreted  in  part  in  the  saliva. 
Concentrated  solutions  may  cause  nausea  and  vomiting  from  their  local 
salt-action  in  the  stomach,  and  their  absorption  is  often  followed  by 
considerable  diuresis  from  a  similar  action  in  the  kidney.  In  the 
great  majority  of  cases  no  further  effects  are  observed. 

In  some  individuals,  however,  symptoms  arise  from  the  chlorate 
action  quite  apart  from  those  mentioned  above,  which  may  be  induced 
by  chloride  of  sodium  or,  in  fact,  by  any  other  diffusible  salt.  (See 
Salt-action,  page  485.)  These  chlorate  symptoms  may  be  divided  into 
those  of  acute  and  of  subacute  poisoning,  the  first  arising  generally  from 
the  administration  of  a  single  large  dose,  the  second  from  smaller 
quantities  taken  repeatedly.  In  Acute  Chlorate  Poisoning  the  first 
symptom  is  often  prolonged  and  violent  vomiting,  with  pain  in  the 
stomach  region  ;  diarrhoea  and  a  dark  eyanotic  color  of  the  skin  and 
mucous  membranes  follow,  the  respiration  is  at  first  dyspnoeic  and  then 
weak,  the  pulse  quick  and  feeble,  sometimes  irregular.  The  patient 


CHLORATES.  523 

complains  of  headache,  giddiness  and  muscular  weakness,  is  restless,  and 
eventually  becomes  comatose  before  death. 

In  Subacute  Poisoning,  vomiting  and  diarrhoea  are  also  observed, 
and  the  vomited  matter  often  contains  large  quantities  of  bile,  less 
often  blood.  There  may  be  complete  anuria  for  some  time,  or  the 
urine  is  scanty  and  at  first  dark  colored,  then  deep  reddish-brown  ; 
it  contains  haemoglobin,  methaemoglobin,  and  haematin  in  solution. 
On  standing,  it  deposits  casts  of  brown  amorphous  particles,  which  arise 
from  the  destruction  of  the  red  cells  of  the  blood,  and  chlorates  are 
contained  in  it  in  considerable  quantity.  The  methaenioglobin  may 
disappear  from  the  urine  after  one  or  two  days,  but  the  casts  re- 
main longer.  The  skin  is  often  icteric  in  color,  and  in  some  cases 
erythematous  eruptions  have  been  observed.  Headache,  muscular  weak- 
ness and  abdominal  pain  are  complained  of,  and  uraemic  symptoms  may 
arise  —  delirium  and  convulsions,  or  confusion  and  coma.  Death  has 
followed  from  these  last  as  late  as  a  week  after  the  first  symptoms  of 
poisoning  were  observed,  but  in  several  cases  complete  recovery  has 
followed  even  the  gravest  symptoms. 

Action. — The  cause  of  the  symptoms  in  acute  and  subacute  chlorate 
poisoning  is,  apart  from  the  salt-action,  a  specific  effect  which  the 
chlorates  have  on  the  Red  Blood  Cells  and  particularly  on  the  Haemoglo- 
bin. This  is  seen  especially  well  when  blood  is  added  to  a  chlorate 
solution  outside  the  body,  for  in  the  course  of  a  short  time  the  blood 
assumes  a  dark  chocolate  brown  color,  and  spectroscopic  examination 
reveals  the  absorption  bands  of  methaemoglobin  and  often  of  haematin. 
After  a  time  the  red  blood  cells  tend  to  break  up,  and  the  methaemoglo- 
bin  is  freed  in  the  serum.  If  large  quantities  of  chlorate  be  added, 
the  blood  becomes  quite  black  in  color,  and  assumes  a  gelatinous  con- 
sistency. This  action  of  chlorates  on  the  blood  arises  from  their  oxi- 
dizing properties,  for  other  oxidizing  agents  have  the  same  effects ; 
the  exposure  of  haemoglobin  to  such  bodies  leads  to  the  formation  of 
methaemoglobin,  while  red  blood  cells  are  destroyed  and  the  haemo- 
globin is  liberated  in  the  plasma.  But  while  the  formation  of  methae- 
moglobin  and  the  haemolysis  are  both  referable  to  oxidation,  the  two 
processes  seem  to  proceed  independently  of  each  other,  for  some  oxi- 
dizing agents  induce  marked  haemolysis  with  little  methaemoglobin, 
while  in  others  the  latter  feature  is  the  predominating  one. 

When  this  transformation  of  the  haemoglobin  takes  place  in  ves- 
sels, the  blood  is  unable  to  supply  the  tissues  with  oxygen,  because  in 
methaemoglobin  the  oxygen  is  attached  much  more  firmly  than  in  oxy- 
haemoglobin,  and  the  tissues  are  incapable  of  availing  themselves  of  it. 
If  much  of  the  haemoglobin  is  thus  rendered  useless,  asphyxia  results, 
and  this  is  unquestionably  the  chief  cause  of  the  symptoms  and  of  the 
fatal  issue  in  the  most  acute  form  of  intoxication.  If  a  smaller  amount 
of  methaemoglobin  is  formed,  it  disappears  gradually,  either  by  being 
slowly  reformed  to  haemoglobin,  or  by  the  corpuscles  containing  it 
being  withdrawn  from  the  circulation  and  broken  up.  When  a  con- 
siderable amount  of  haemoglobin  is  transformed,  but  sufficient  remains 


524  INORGANIC  SALTS,  ACIDS  AND  BASES. 

to  continue  the  respiration  of  the  tissues,  the  subacute  form  of  poison- 
ing results.  The  blood  cells  break  up  and  the  haemoglobin,  methaamo- 
globin  and  the  debris  of  the  corpuscles  thus  freed  in  the  plasma  are 
in  part  excreted  by  the  urine,  in  part  deposited  in  the  spleen,  liver, 
and  bone  marrow.  As  in  other  conditions  of  excessive  destruction  of 
the  red  blood  cells,  the  bile  pigment  is  increased  in  amount,  and  its 
absorption  from  the  bile  capillaries  induces  jaundice.  The  excretion 
of  the  products  of  the  destruction  of  the  red  blood  corpuscles  in  the 
urine  leads  to  the  renal  tubules  becoming  stopped  up  with  brown 
granular  masses,  which  are  in  part  forced  downwards  and  appear  in 
the  urine  as  casts,  but  which  may  lead  to  an  almost  complete  suppres- 
sion of  urine  and  to  symptoms  of  ursemic  poisoning.  In  those  cases  in 
which  death  follows  several  days  after  the  first  symptoms,  it  seems  due 
not  to  the  direct  action  of  the  poison,  but  to  the  renal  changes.  Often 
no  actual  nephritis  is  present,  but  in  some  cases  the  epithelial  cells 
seem  to  be  inflamed,  probably  as  a  secondary  result  of  the  plugging 
of  the  tubules.  The  deposition  of  the  debris  in  the  liver  and  spleen 
often  causes  enlargement  of  these  organs.  In  these  subacute  cases  of 
poisoning,  then,  death  is  not  due  directly  to  the  methsemoglobin  for- 
mation, but  to  the  breaking  down  of  the  red  cells. 

The  post-mortem  appearances  in  chlorate  poisoning  vary  with  the 
form.  In  acute  poisoning  the  characteristic  color  of  the  blood,  and 
the  methsemoglobin  absorption  band  in  the  spectrum  are  often  the  only 
distinct  appearances.  In  less  acute  cases,  the  debris  of  the  red  cor- 
puscles is  found  in  the  liver,  spleen,  bone-marrow  and  renal  tubules, 
while  no  methsemoglobin  may  be  detected.  Some  of  the  red  blood 
corpuscles  are  found  misshapen,  however,  others  are  colorless  (shadows), 
and  in  some  the  pigment  is  formed  in  masses,  instead  of  being  gener- 
ally diffused.  Some  swelling  and  ecchymoses  of  the  gastric  and  in- 
testinal mucous  membrane  have  been  observed. 

It  has  been  recently  stated  that  some  of  the  symptoms  of  chlorate 
poisoning  are  due  to  infarcts  formed  in  the  smaller  vessels  from  the 
agglutination  of  the  remains  of  the  red-blood  cells,  and  Silbermann 
has  even  failed  to  inject  some  parts  of  the  body  owing  to  this  plugging 
of  the  arteries.  This  statement  has  been  denied,  however,  by  Mar- 
chand  and  Falkenberg,  who  could  find  no  evidence  of  such  infarction. 

The  haemoglobin  of  most  animals  seems  equally  easily  transformed 
to  methsemoglobin  by  chlorates  when  it  is  dissolved  in  water,  but  the 
blood  corpuscles  of  the  rabbit  and  guinea-pig  resist  their  action  much 
more  than  do  those  of  the  dog  and  of  man.  Rabbits  therefore  very 
rarely  show  any  symptoms  of  true  chlorate  action,  and  die  of  the 
potassium  or  of  the  salt-action,  while  dogs  and  cats  exhibit  symptoms 
very  like  those  seen  in  man.  The  cause  of  this  immunity  of  the 
rabbit's  corpuscles  is  unknown,  but  may  perhaps  be  explained  by  their 
being  impermeable  by  the  chlorate  salts.  It  has  been  found  that  when 
the  rabbit's  blood  is  concentrated,  or  when  bile  is  present  in  quantity 
in  it,  the  chlorate  action  may  be  elicited  much  more  readily  than  in 
normal  animals. 


CHLORATES.  525 

The  nervous  symptoms  in  chlorate  poisoning  are  manifestly  due  to 
the  blood  changes  and  the  uraemia  for  the  most  part,  though  there  is 
reason  to  believe  that  under  some  conditions  the  brain  is  also  directly 
affected.  The  heart  is  said  to  be  first  slowed  and  then  accelerated  by 
the  intravenous  injection  of  sodium  chlorate.  The  vomiting  does  not 
seem  to  be  due  to  local  action  only,  for  it  is  seen  in  animals  in  which 
the  salt  is  injected  subcutaneously. 

Very  little  chlorate  is  reduced  in  the  blood  and  tissues,  for  90-96 
per  cent,  of  the  amount  administered  has  been  recovered  from  the 
urine.  Small  quantities  appear  also  in  the  saliva  and  in  other  secre- 
tions, such  as  the  perspiration,  milk,  tears,  and  nasal  mucus,  and  some 
has  been  found  to  pass  from  the  mother  to  the  foetus  in  utero. 

The  chlorates  are  hardly  more  antiseptic  than  other  indifferent 
salts. 

The  Bromates  and  lodates  have  been  much  more  seldom  the  subject  of  in- 
vestigation than  the  chlorates,  and  are  not  used  in  therapeutics.  The  iodates  are 
more  poisonous  than  the  bromates  and  these  again  than  the  chlorates  ;  the  iodates 
destroy  the  red  cells  more  rapidly  but  form  less  methaBinoglobin  than  the  chlo- 
rates in  test-tube  experiments.  lodates  induce  fatty  degeneration  of  the  liver,  and 
congestion  and  extravasation  in  the  alimentary  tract.  It  is  not  unlikely  that 
some  iodide  is  formed  from  them  in  the  body. 

The  action  of  the  Perchlorates  has  been  examined  by  Kerry  and  Host. 
In  the  frog  the  perchlorate  of  sodium  (NaClOJ  induces  fibrillary  twitching 
and  clonic  contractions  of  the  muscles  ;  the  contraction  of  the  muscle  is  pro- 
longed in  the  same  way  as  by  veratrine,  and  rigor  eventually  follows  as  in 
caffeine  poisoning.  The  reflex  excitability  is  increased,  and  the  heart  is  slow 
and  irregular.  The  effects  of  the  perchlorate  on  mammals  differ  consider- 
ably in  different  species  ;  in  the  rat,  mouse  and  guinea-pig  the  reflex  excita- 
bility is  enormously  increased  and  tetanic  convulsions  may  arise  from  this 
action  ;  in  the  cat  a  certain  stiffness,  muscular  paresis  and  tremor  can  be 
made  out  after  the  injection  of  large  quantities  of  perchlorate,  but  these 
animals  as  well  as  the  rabbit  and  dog  are  not  killed  by  even  very  large 
quantities. 

PREPARATIONS. 

POTASSII  CHLORAS  (U.  S.  P.,  B.  P.)  (KC1O3),  0.3-1  G.  (5-15  grs.). 

TROCHISCI  POTASSII  CHLORATIS  (U.  S.  P.)  contain  0.3  G.  (5  grs.)  chlorate 
of  potassium  in  each  lozenge. 

TROCHISCUS  POTASSII  CHLORATIS  (B.  P.)  contains  3  grs.  in  each. 

Sodii  Chloras  (U.  S.  P.)  (NaClO3),  0.5-2  G.  (10-30  grs.). 

The  chlorates  are  colorless  prismatic  crystals  with  a  saline  taste,  and  are 
given  in  solution  or  in  lozenges  when  used  internally.  The  dry  salts  form 
explosive  mixtures  with  organic  or  other  reducing  substances,  and  such 
mixtures  are  therefore  to  be  kept  cool,  and  ought  not  to  be  ground  together, 
as  heat  and  pressure  are  liable  to  cause  explosions. 

Therapeutic  Uses. — The  chlorate  of  potassium  is  used  chiefly  as  a 
mouth  wash  and  gargle  in  irritable  conditions  of  the  mouth  and  throat, 
such  as  aphthe,  and  in  the  tenderness  and  ulceration  of  the  gums  and 
mouth  induced  by  the  prolonged  use  of  mercury.  It  may  also  be 
given  as  a  prophylactic  to  prevent  stomatitis  when  mercury  is  being 
prescribed,  but  it  does  not  prevent  the  salivation.  In  catarrh  of  the 
throat  the  chlorate  of  potassium  is  often  used  with  apparently  good 


526  INORGANIC  SALTS,   ACIDS  AND  BASES. 

effects.  It  has  been  strongly  advised  in  diphtheria,  but  is  of  only 
questionable  value  here. 

The  chlorate  of  potassium  is  more  frequently  prescribed  than  the 
sodium  salt,  but  the  latter  seems  equally  efficient.  The  chlorates  are 
used  in  2-4  per  cent,  solution,  or  the  official  lozenge  may  be  prescribed. 
In  children  a  somewhat  stronger  solution  with  syrup  or  honey  may  be 
used  to  brush  out  the  mouth,  but  care  should  be  taken  that  none  is 
swallowed.  The  local  action  of  the  chlorates  has  not  been  explained, 
and  it  may  be  due  to  the  salt-action  in  part,  though  not  wholly.  It  has 
been  suggested  that  they  are  oxidizing  disinfectants,  but  there  is  no 
reason  to  suppose  that  they  are  changed  here  any  more  than  in  the  tis- 
sues in  general.  It  is  not  impossible  that  equally  satisfactory  results 
might  be  obtained  by  the  use  of  the  chlorides  or  nitrates.  Chlorate  of 
potassium  has  been  given  internally  in  cases  of  diphtheria  and  in  some 
diseases  of  the  mouth,  but  it  does  not  seem  to  have  any  therapeutic 
value  unless  when  applied  locally.  Some  benefit  may  arise  from  its 
contact  with  the  mouth  and  throat  in  the  process  of  swallowing  and 
from  its  excretion  in  the  saliva.  In  addition  the  internal  administra- 
tion of  the  chlorate  is  liable  to  induce  dangerous  poisoning.  It  is  un- 
necessary to  discuss  the  earlier  uses  of  the  chlorate,  which  were  based 
on  the  theory  that  it  gave  up  its  oxygen  to  the  blood,  for  both  theory 
and  practice  have  been  shown  to  be  erroneous. 

Poisoning.  —  The  fatal  dose  of  chlorate  varies  extremely,  as  little  as 
1  G.  (15  grs.)  having  proved  fatal  in  a  child,  while  40-50  G.  (10-12 
drs.)  have  been  swallowed  by  adults  without  marked  symptoms.  There 
is  no  question  that  the  red  blood  cells  are  often  peculiarly  susceptible 
to  the  action  of  the  chlorates ;  poisoning  is  especially  common  in 
nephritis.  In  cases  of  poisoning  the  stomach  should  be  evacuated,  if 
any  of  the  salt  is  believed  to  remain  in  it,  but  the  symptoms  often 
appear  only  2-3  hours  or  longer  after  the  drug  has  been  taken. 
General  treatment  with  central  nervous  stimulants,  ice  for  the  vomit- 
ing, etc.,  may  be  carried  out.  The  formation  of  methsemoglobin  is  less 
liable  to  occur  when  the  blood  is  more  alkaline  than  usual,  and  this  has 
led  to  the  administration  of  the  alkaline  carbonates  in  these  cases. 
After  the  acute  symptoms  pass  off  diuretics  are  often  advised,  and  large 
quantities  of  fluid  are  given  in  order  to  flush  out  the  kidneys  and  pre- 
vent as  far  as  possible  the  tubules  from  being  stopped  up  by  detritus. 

BIBLIOGRAPHY. 

Marchand.  Virchow's  Arch.,  Ixxvii.,  p.  455.  Arch.  f.  exp.  Path.  u.  Pharm.t 
xxii.,  p.  201  ;  xxiii.,  pp.  273  and  347. 

Mering.     Das  chlorsaure  Kali,  1885,  Berlin. 

Stokvis.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxi.,  p.  169. 

Cahn.     Ibid.,  xxiv.,  p.  180. 

Leurin  u.  Posner.     Centralbl.  f.  d.  med.  Wissensch.,  1887,  p.  354. 

Dittrich.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix.,  p.  247. 

Silbermann.     Virchow's  Arch.,  cxvii.,  p.  288. 

Falkenberg.     Ibid.,  cxxiii.,  p.  577. 

Binz.     Arch.  f.  exp.  Path.  u.  Pharm.,  x.,  p.  153;  xxxiv.,  p.  185. 

Jawein.     Virchow's  Arch.,  clxi.,  p.  461. 


NITRATES.  527 

Falck.     Pfliiger's  Arch.,  xlv.,  p.  304. 

Dreser.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv.,  p.  204.     (lodates,  Bromates.) 

Kerry  u.  Host.     Ibid.,  xxxix.,  p.  144.     (Perchlorates.) 

Mathews.     Amer.  Journ.  of  Physiol.,  xi.,  p.  237. 

X.     NITRATES. 

The  nitrates  are  generally  supposed  to  have  little  action  except  that 
of  salts  in  general,  and  have  been  comparatively  seldom  the  subject  of 
pharmacological  examination.  In  small  doses  they  induce  changes 
very  similar  to  those  seen  after  the  chlorides,  but  there  is  little  doubt 
that  in  addition  to  the  salt-action,  a  distinct  nitrate-ion  effect  exists, 
and  is  manifested  chiefly  in  irritation  of  the  mucous  membranes  which 
are  exposed  to  it. 

Symptoms. — The  nitrates  have  a  cool,  saline  taste,  and  in  small 
doses  induce  no  symptoms  save  an  augmented  flow  of  urine.  Large 
quantities,  however,  cause  gastro-intestinal  irritation,  giving  rise  to 
pain  in  the  stomach  region,  nausea,  vomiting  and  sometimes  diarrhrea, 
and  blood  may  be  present  in  the  vomited  matter  and  in  the  stools. 
The  urine  is  often  abundant,  but  may  be  scanty  or  entirely  suppressed. 
These  symptoms  may  be  followed  by  great  muscular  weakness,  apathy, 
collapse  and  eventually  coma  and  death. 

At  the  autopsy  the  stomach  and  intestines  are  found  red  and  con- 
gested, and  very  often  contain  blood  extravasations.  The  kidney  is 
said  to  have  presented  the  symptoms  of  acute  nephritis  and  haemor- 
rhages in  some  cases  of  poisoning. 

When  dilute  solutions  of  the  nitrates  are  used,  much  less  irritation 
is  induced,  and  in  fact  large  quantities  may  be  taken  thus  without 
causing  any  symptoms  whatever  except  diuresis. 

Action.  —  Very  similar  effects  may  be  induced  by  large  quantities  of 
common  salt,  or  of  potassium  chloride,  and  it  is  therefore  often  stated 
that  the  nitrates  act  in  the  same  way  as  the  chlorides.  But  this  is  not 
entirely  correct,  for  while  there  is  no  question  that  the  salt-action  ex- 
plains much  of  the  effect  of  the  nitrates,  these  salts  have  a  specific 
irritant  action.  Thus  very  much  smaller  quantities  of  the  nitrates 
than  of  the  chlorides  are  sufficient  to  induce  serious  irritation,  and 
solutions  of  the  nitrates  isotonic  with  the  blood  induce  irritation  and 
congestion  in  the  intestine  and  are  slowly  absorbed.  This  irritant 
effect  of  the  nitrates  has  been  explained  by  Binz  and  Barth  as  the 
result  of  the  reduction  of  the  nitrates  to  nitrites  in  the  alimen- 
tary canal  and  tissues,  but  no  symptoms  of  nitrite  action  seem 
to  have  been  observed  in  cases  of  poisoning  with  nitrates.  Haldane 
has  recently  shown  that  nitrite  is  formed  from  the  nitrate  used  in 
the  preservation  of  meat  by  salting,  and  that  some  nitrous-oxide 
haemoglobin  is  formed  and  gives  a  bright  red  color  to  the  meat. 
The  presence  of  this  pigment  may  perhaps  explain  the  red  color  of 
the  intestine  in  some  cases  of  poisoning  in  which  extravasations  of 
blood  are  not  marked. 


528  INORGANIC  SALTS,   ACIDS  AND  BASES. 

The  nitrates  have  long  been  used  as  diuretics,  more  especially  th 
nitrate  of  potassium.  The  diuresis  is  generally  attributed  to  the  salt 
action,  but  there  may  be  in  addition  a  true  stimulation  of  the  kidne; 
similar  to  that  observed  under  the  action  of  many  other  drugs  whicl 
are  irritant  to  the  bowel.  If  WeyPs  statement  be  correct  that  th 
nitrates  of  the  urine  are  not  increased  by  the  administration  of  nitrate 
by  the  mouth,  the  diuresis  must  be  due  to  some  stimulant  action  onlj 
The  nitrate  of  potassium  is  generally  considered  a  better  diuretic  thai 
the  sodium  salt. 

The  Fate  of  the  Nitrates  in  the  Body  is  still  unknown,  and  in  fac 
seems  to  vary  in  different  animals  and  under  different  conditions.  I: 
man  and  in  most  animals,  some  nitrate  is  present  in  the  urine  normally 
apparently  derived  from  vegetable  food,  although  it  may  in  some  case 
be  one  of  the  final  products  of  the  proteid  metabolism.  Large  dose 
of  nitrates  given  by  the  mouth  lead  to  some  increase  in  the  nitrate  ii 
the  urine,  although  more  than  half  of  that  ingested  disappears  entirel 
in  the  tissues.  Nitrite  has  also  been  found  in  the  urine  after  larg 
quantities  of  nitrates  in  animals  and  the  nitrite  reaction  is  obtained  froc 
a  number  of  organs.  When  smaller  amounts  of  nitrate  are  swallowe< 
(1—3  G.  in  man),  no  increase  in  the  nitrate  of  the  urine  is  observed 
the  whole  of  that  ingested  being  changed  to  some  other  form  in  th 
tissues.  It  is  surmised  that  the  nitrate  is  reduced  first  to  the  nitrite 
and  then  to  ammonia,  or  that  it  is  eventually  excreted  by  the  lungs  a 
free  nitrogen.  Some  of  the  nitrate  seems  to  be  excreted  in  the  saliv 
and  perspiration,  possibly  unchanged,  although  it  is  rapidly  reduced  t 
nitrite  in  these  secretions,  and  may  in  fact  be  changed  to  this  form  i 
the  secretory  cells. 

The  action  of  the  nitrates  on  the  individual  organs  is  practicall 
entirely  unknown.  They  have  a  weak  ha?molytic  effect  in  th 
blood. 

Richet  has  found  solutions  of  the  nitrate  of  sodium  less  harmful  t 
fish  living  in  it  than  those  of  any  other  salt  except  the  chloride. 

PREPARATIONS. 

Potasii  Nitras  (U.  S.  P.,  B.  P.),  Nitre,  Saltpetre  (KN03),  0.3-2  G.  (5-3 
grs.). 

Sodii  Nitras  (U.  S.  P.),  Chili  Saltpetre  (NaNO3),  0.3-2  G.  (5-30  grs.). 

The  nitrates  form  colorless  crystals  with  a  cool,  saline  taste.  They  ar 
very  soluble  in  water  and  are  prescribed  in  dilute  solution. 

Therapeutic  Uses.  —  The  nitrates  are  seldom  used  now  except  as  in 
gredients  of  diuretic  mixtures  ;  e.  g.,  along  with  digitalis.  The  nitrat 
of  potassium  was  formerly  employed  largely  in  fevers  and  in  variou 
disorders  of  the  metabolism,  such  as  rheumatism  or  gout,  but  in  none  oJ 
these  has  it  been  found  useful.  The  nitrates  are  to  be  given  with  can 
when  there  is  any  irritation  of  the  stomach  and  intestine.  Authorities 
differ  as  to  whether  they  may  be  prescribed  in  irritation  of  the  kidney 
but  in  every  case  they  ought  to  be  well  diluted. 


SULPHITES.  529 

Paper  impregnated  with  saltpetre  is  used  in  asthma  by  burning  it  in 
the  sick  room,  when  the  pyridine  and  nitrites  relieve  the  spasms 
by  relaxing  the  bronchial  muscles.  Saltpetre  may  be  used  in  cigars  or 
cigarettes  for  the  same  purpose,  and  the  tobacco  may  contain  also  the 
leaves  of  belladonna  or  some  of  its  allies,  as  these  have  a  special  action 
on  the  bronchial  muscle. 

BIBLIOGRAPHY. 

Binz  et  Gerlinfjer.     Arch,  internal,  de  Pharmacodyn.,  ix.,  p.  441. 

Littlejohn.     Edinburgh  Med.  Journ.,  1885,  p.  97. 

Eoehmann.     Zts.  f.  Physiol.  Chem.,  v.,  p.  233. 

Weyl.     Virchow's  Arch.,  xcvi.,  p.  462 ;  ci.,  p.  175  ;  cv.,  p.  187. 

Rfchet.     Comptes  rend.  d.  1.  Soc.  de  Biol.,  1886,  xxxviii.,  p.  486. 

Heffter.     Ergebnisse  der  Physiologic,  ii.,  1,  p.  112. 

Haldane.     Journ.  of  Hygiene,  i.,  p.  115. 

Eost.     Arch.  f.  [Anat.  u.j  Physiol.,  1901,  p.  534. 

XI.     SULPHITES. 

The  sulphites,  an  unimportant  group  of  bodies  from  a  therapeutic  point 
of  view,  have  been  shown  to  have  a  more  poisonous  action  than  many  better 
known  salts.  They  possess  fairly  strong  antiseptic  properties,  because  they 
withdraw  oxygen  from  organic  matter  in  order  to  oxidize  themselves  to  sul- 
phates. Injected  into  frogs,  sulphite  of  soda  causes  great  muscular  weak- 
ness and  depression,  and  eventually  paralysis  of  the  central  nervous  system, 
beginning  in  the  brain  and  descending  to  the  spinal  cord.  Later,  the  heart 
becomes  weak  and  ceases  in  diastole,  and  the  peripheral  nerve  terminations 
and  the  muscles  are  paralyzed.  In  mammals  the  action  is  exerted  chiefly 
on  the  medulla  oblongata  and  the  heart.  In  the  dog  and  cat  subcutaneous 
injection  causes  nausea,  vomiting,  restlessnesss  and  dyspnoea  and  great 
muscular  weakness,  ending  in  arrest  of  the  respiration,  and  a  little  later  of 
the  heart.  In  the  rabbit  the  symptoms  consist  of  dyspnoea,  muscular  weak- 
ness without  loss  of  spontaneous  movements,  and  finally  death  from  failure 
of  the  respiration  and  the  heart. 

Much  larger  quantities  are  required  to  poison  animals  when  given  by  the 
mouth  than  when  injected  subcutaneously,  probably  because  the  salt  is 
slowly  absorbed  from  the  alimentary  tract,  and  also  because  some  of  it  is 
changed  to  the  harmless  sulphate  before  it  reaches  the  blood.  Some  irri= 
tation  of  the  stomach  is  caused  from  the  sulphurous  acid  being  freed  by  the 
gastric  juice,  and  this  induces  vomiting  in  the  dog. 

Intravenous  injection  shows  that  the  chief  seat  of  action  of  the  sulphites  is 
the  medulla  oblongata,  in  which  they  depress  the  respiratory  and  vasomotor 
centre 5.  The  heart  is  acted  on  directly  apparently,  for  the  pulse  is  slow, 
and  the  muscular  walls  of  the  vessels  are  also  weakened.  Kionka  states 
that  sulphites  destroy  the  red  cells  of  the  blood,  and  that  infarcts  are  formed 
from  their  remains  in  the  vessels  and  lead  to  haemorrhages  in  many  organs. 

If  large  quantities  be  absorbed  rapidly,  they  prove  immediately  fatal,  but 
if  the  respiration  be  kept  up  for  a  short  time,  recovery  may  follow,  because 
the  poisonous  sulphite  is  changed  to  the  harmless  sulphate  and  excreted. 
About  96  per  cent,  of  the  sulphite  absorbed  into  the  blood  is  oxidized  to  the 
sulphate,  while  some  3  per  cent,  is  excreted  in  the  urine  unchanged.  The 
thiosulphate  is  apparently  oxidized  with  greater  difficulty,  for  Walko  found 
30-50  per  cent,  eliminated  by  the  kidneys  unaltered. 

Large  doses  of  sulphites  have  been  taken  by  man  without  symptoms  of 

poisoning  being  induced.     Even  30-40  gms.  are  said  to  have  been  swallowed, 

but  in  most  preparations  of  sulphite  a  large  proportion  of  sulphate  is  pres- 

int,  and  it  is  impossible  to  state  how  much  sulphite  was  really  contained  in 

34 


530  INORGANIC  SALTS,  ACIDS  AND  BASES. 

these  doses.  Symptoms  of  gastric  and  intestinal  irritation  have  been  in- 
duced by  comparatively  small  quantities,  and  Kionka  found  that  even  smaller 
doses  of  sulphite  administered  daily  to  animals  caused  hemorrhages  in  dif- 
ferent organs,  and  accordingly  condemns  the  use  of  sulphites  to  preserve 
meat,  wines  and  vegetables  ;  in  addition  they  seem  to  have  little  effect  in 
preserving  meat  from  putrefaction  though  they  improve  its  appearance. 

^  Sodii  Sulphis  (XL  S.  P.,  B.  P.)  (Na2SO3  +  7H2O),  a  soluble  salt  which  oxi- 
dizes to  the  sulphate  in  the  air,  is  feebly  alkaline  and  has  a  cool,  saline 
taste.  0.3-2  G.  (5-30  grs.). 

Sodii  Bisulphis  (U.  S.  P.)  (NaHSO3)  has  a  disagreeable  odor  of  sulphurous 
acid,  an  unpleasant  taste  and  an  acid  reaction.  1-2  G.  (15-30  grs.). 

Sodii  Thiosulphas  (U.  S.  P.)  (Na2S2O3  +  5H2O)  is  very  soluble,  has  a  cool, 
saline  taste  and  is  neutral  in  reaction.  1-2  G.  (15-30  grs.). 

Solutions  of  these  salts  have  been  used  to  a  limited  extent  as  antiseptic 
mouth-washes  in  aphthe,  and  have  been  prescribed  in  some  forms  of  fermen- 
tation in  the  stomach.  They  were  formerly  reputed  to  be  of  benefit  in  cases 
of  pyaemia  from  their  supposed  action  as  antiseptics  in  the  blood,  but  have 
never  been  shown  to  be  of  any  real  value. 

BIBLIOGRAPHY. 

Pfeiffer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii.,  p.  261. 

Kionka.     Ztschr.  f.  Hygiene,  xxii.,  p.  351  ;  xli.,  p.  123. 

Walko.     Arch,  de  Pharmakodynam.,  iv.,  p.  311. 

Lange.     Arch.  f.  Hygiene,  xl.,  p.  143. 

Rout  u.  Franz.     Arb.  a.  d.  K.  Gesundheitsamte,  xxi.,  p.  312. 

Altsch'dler.     Arch.  f.  Hygiene,  xlviii.,  p.  114. 

XII.     HYPOPHOSPHITES. 

The  hypophosphites  have  been  used  in  therapeutics  in  the  belief  that  they 
had  some  special  influence  on  nutrition.  They  were  formerly  supposed  to 
be  oxidized  in  the  tissues  to  the  phosphates,  but  this  has  been  shown  to  be 
incorrect,  as  practically  the  whole  of  the  hypophosphite  administered  can 
be  recovered  unchanged  from  the  urine.  No  entirely  satisfactory  work  on 
the  effects  of  these  salts  on  the  nutrition  has  been  done,  but  there  is  no 
ground  to  suppose  that  they  have  any  further  action  than  the  other  indif- 
ferent salts,  such  as  the  chlorides.  The  chief  effect  of  the  hypophosphite  of 
iron  is  undoubtedly  due  to  the  metallic  ion. 

PREPARATIONS. 

Sodii  Hypophosphis  (NaOPH2O)  (U.  S.  P.,  B.  P.),  0.2-0.6  G.  (3-10  grs.). 

Potassii  Hypophosphis  (KOPH2O)  (U.  S.  P.),  0.2-0.6  G.  (3-10  grs.). 

Calcii  Hypophosphis  (Ca(OPH2O)2)  (U.  S.  P.,  B.  P.),  0.2-0.6  G.  (3-10  grs.). 

Ferri  Hypophosphis  (Fe2(OPH2O)6)  (U.  S.  P.),  0.2-0.6  G.  (3-10  grs.). 

AcidumHypophosphorosum  (U.  S.  P.),  0.5  c.c.  (8  mins.). 

Syrupus  Hypophosphitum  (U.  S.  P.)  contains  the  hyphophosphites  of  cal- 
cium, potassium,  sodium,  free  hypophosphorous  acid,  spirit  of  lemon  and  sugar, 
4-8  c.c.  (1-2  fl.  drs.). 

Syrupus  Hypophosphitum  Compositus  (U.  S.  P.)  contains,  in  addition  to  the 
constituents  of  the  above,  iron,  manganese,  quinine,  strychnine,  and  sodium 
citrate.  8  c.c.  (2  fl.  drs.). 

Therapeutic  Uses. — The  hypophosphites  are  used  in  weakness  and  ca- 
chexia,  and  especially  in  commencing  phthisis  and  anemia.  The  syrup  with 
or  without  iron  is  the  form  in  which  they  are  invariably  prescribed.  There 
is  a  popular  belief  that  they  improve  digestion  and  nutrition,  but  most  re- 
liable investigators  deny  that  they  have  any  other  influence  than  the  better 
known  and  cheaper  salts  of  iron,  calcium,  etc. 


SALINE  CATHARTICS.  531 

BIBLIOGRAPHY. 

Paqudin  et  Joly.     Comptes  rendus  de  1'Acad.  d.  Science,  Ixxxvi.,  p.  1505. 

Taylor.     Lancet,  1861,  ii.,  p.  517. 

Boddaert.     Arch.  d.  Pharmacodynam.,  ii.,  p.  195. 

Gamier.     Kev.  Med.  de  Test,  1896,  p.  257. 

XIII.     SALINE    CATHARTICS, 

Dilute  solutions  of  such  salts  as  the  chlorides,  iodides  and  bromides 
of  the  alkalies  are  absorbed  rapidly  from  the  alimentary  canal,  but 
some  of  the  other  salts  of  these  metals  apparently  permeate  the  epi- 
thelium with  greater  difficulty,  and  their  solutions  therefore  remain 
unabsorbed  for  a  longer  time  in  the  intestine.  Little  is  known  of  the 
effects  of  these  salts  in  the  tissues,  but  their  action  in  the  intestine 
has  led  to  their  therapeutic  use,  and  they  may  therefore  be  classed  to- 
gether as  the  saline  cathartics,  in  order  to  distinguish  them  from  the 
rapidly  absorbed  salts,  such  as  the  chlorides,  or  bromides.  The  chief 
salts  of  sodium  and  potassium  which  have  this  intestinal  action  are  the 
sulphates,  phosphates,  tartrates  and  citrates  ;  less  known  ones  are  the 
malates  and  ferrocyanides. 

It  is  manifest  that  the  peculiar  effect  of  these  salts  is  due  to  the 
acid  constituent,  or  anion,  and  not  to  the  base  or  kation,  for  the  latter 
may  be  present  in  readily  absorbable  salts,  such  as  chlorides.  All 
combinations  in  which  the  sulphate,  phosphate,  etc.,  ion  is  found, 
therefore,  are  less  easily  absorbed  than  the  corresponding  ones  with 
bromide  or  chloride  ions.  But  these  cathartic  anions  are  only  weakly 
active,  and  no  pronounced  difference  can  be  observed  in  the  action  of 
chlorides  and  sulphates,  unless  the  salt  can  be  given  in  large  quanti- 
ties, as  is  possible  in  the  case  of  the  salts  of  the  alkalies.  The  effects 
of  the  sulphate  and  hydrochlorate  of  morphine,  for  example,  may  be 
taken  as  identical,  because  the  anion  is  present  in  so  small  amount  as 
to  be  practically  inert. 

The  chloride  ion  is  rapidly  absorbed,  as  is  seen  in  the  case  of  sodium 
chloride.  Yet  when  the  chloride  of  magnesium  is  administered,  it 
disappears  only  very  slowly  from  the  bowel.  It  would  seem,  there- 
fore, that  the  magnesium  is  also  more  slowly  absorbed  than  the  sodium 
and  potassium  ions,  and  that  cathartic  action  can  be  obtained  from 
either  basic  ions  (kations)  or  from  acid  ions  (anions).  When  both 
ions  of  a  salt  are  slowly  absorbed,  the  cathartic  is,  of  course,  more  power- 
ful than  when  one  is  rapidly  absorbed.  Thus,  magnesium  sulphate  is 
a  more  powerful  purgative  than  either  magnesium  chloride  or  sodium 
sulphate,  because  in  the  first  both  ions  are  difficult  of  absorption,  while 
in  the  others  only  one  is  cathartic.  It  seems  probable  that  all  the 
alkaline  earth  ions  resemble  magnesium  in  permeating  the  epithelium 
with  difficulty. 

The  chief  saline  cathartics  used  in  therapeutics  are  the  sulphate  of 
sodium  (Glauber's  salt),  the  sulphate  of  magnesium  (Epsom  salt),  the 
double  tartrate  of  sodium  and  potassium  (Rochelle  salt)  and  the  ci- 
trates of  potassium  and  magnesium.  In  addition  the  oxide  and  car- 


532  INORGANIC  SALTS,   ACIDS  AND  BASES. 

bonate  of  magnesium  have  some  purgative  action  from  being  formed 
into  soluble  salts  in  the  stomach  and  intestine.  But  besides  these 
many  other  salts  are  slowly  absorbed  and  might  therefore  be  used  for 
this  purpose.  Thus  the  sulphates,  citrates,  or  tartrates,  of  any  of  the 
alkalies  or  of  the  non-poisonous  alkaloids  might  be  used  for  this  purpose, 
provided  they  are  soluble,  and  any  of  the  magnesium  salts  might  be 
used  in  the  same  way. 

Symptoms.  —  The  external  application  of  solutions  of  the  saline 
cathartics  has  the  same  effect  as  that  of  any  other  indifferent  salt,  such 
as  sodium  chloride  (see  page  491). 

Most  of  the  cathartics  have  a  harsh,  bitter,  unpleasant  taste,  and 
when  taken  in  concentrated  solution,  may  induce  some  nausea,  partly 
from  the  taste,  and  partly  from  their  effect  on  the  stomach,  which  is 
the  same  as  that  of  solutions  of  sodium  chloride  of  similar  concentra- 
tion. Dilute  solutions,  however,  provoke  no  such  symptoms,  but  after 
one  or  two  hours  induce  a  profuse  watery  evacuation  of  the  bowels. 
This  is  sometimes  preceded  by  some  pain  and  griping,  but  these  are 
not  nearly  so  frequent  or  so  severe  as  after  the  vegetable  purgatives. 
Not  infrequently  the  urine  is  increased  in  amount  afterwards,  or  it  may 
be  found  to  have  an  unusually  high  percentage  of  salts.  If  a  moderate 
quantity  of  a  dilute  solution  be  given,  only  one  evacuation  follows,  but 
large  doses  of  concentrated  solutions  induce  repeated  stools,  which  at 
first  contain  some  faecal  matter,  but  later  consist  mainly  of  bile-stained 
mucous  fluid. 

Action  :  Intestine.  —  The  explanation  of  the  action  of  the  saline 
cathartics  has  been  much  debated,  and  the  details  have  not  even  yet 
been  entirely  settled.  One  point  is,  however,  perfectly  certain  —  the 
saline  cathartics  differ  from  the  vegetable  purgatives  in  not  inducing 
irritation  of  the  intestine,  unless  when  they  are  given  in  very  large 
quantities.  The  characteristic  effect  is  not  irritation,  but  retarded  ab- 
sorption. If  a  solution  of  sodium  chloride  isotonic  with  the  blood 
serum  be  administered  by  the  mouth  to  a  dog  with  a  caBcal  fistula, 
little  or  none  of  it  reaches  the  wound,  as  it  is  all  absorbed  in  the 
stomach  and  small  intestine.  If,  on  the  other  hand,  an  equal  amount 
of  an  isotonic  solution  of  sodium  sulphate  be  administered  in  the 
same  way,  the  most  of  the  solution  escapes  by  the  fistula,  only  some 
10-20  per  cent,  having  been  absorbed  by  the  stomach  and  small  in- 
testine. In  a  normal  dog  or  in  the  human  subject,  £  much  larger 
amount  of  fluid  therefore  reaches  the  large  intestine  if  sodium  sulphate 
be  dissolved  in  it  than  if  sodium  chloride  be  used  instead.  The  con- 
tents of  the  large  intestine  are  consequently  more  fluid  than  usual,  and 
are  passed  down  more  easily  towards  the  rectum.  At  the  same  time 
the  weight  and  distention  of  the  bowel  induces  increased  peristalsis 
and  the  whole  is  evacuated.  This  increased  peristalsis  is  due,  how- 
ever, not  to  any  irritant  action  such  as  has  been  found  to  be  induced 
by  rhubarb  or  croton  oil,  but  to  the  large  amount  of  fluid  contents. 

If  a  weaker  solution  of  sodium  sulphate  is  administered,  the  only 
difference  is  that  more  of  the  fluid  is  absorbed  and  less  reaches  the 


SALINE  CATHARTICS.  533 

large  intestine ;  but  however  weak  the  solution,  more  of  it  reaches  the 
large  intestine  than  if  a  correspondingly  weak  solution  of  common  salt 
had  been  given. 

If  a  hypertonic  solution  be  administered,  the  effect  is  somewhat 
different.  The  salt  is  still  unabsorbed,  but  it  draws  fluid  from  the 
blood  into  the  bowel  from  its  having  a  higher  osmotic  pressure  than 
the  blood.  A  similar  draining  of  the  body  fluids  occurs  when  con- 
centrated solutions  of  common  salt  reach  the  bowel,  but  the  cathartic 
salts  are  much  more  powerful,  because  they  do  not  pass  out  of  the  bowel 
into  the  blood  so  easily.  Instead  of  an  exchange  of  salt  and  fluid 
being  carried  on  by  the  blood  and  intestinal  contents,  the  blood  gives 
up  its  fluid  without  any  sufficient  compensation  in  salt.  Eventually 
the  intestinal  fluid  becomes  isotonic,  and  then  some  absorption  of  both 
salt  and  fluid  occurs ;  in  fact,  some  salt  has  been  absorbed  all  along,  as 
the  epithelium  is  not  absolutely  impermeable  to  the  cathartics.  But 
much  less  of  the  sulphate  is  absorbed  than  of  the  chloride  given  in 
equal  concentration,  and  as  a  general  rule  a  strong  solution  causes 
such  an  accumulation  of  fluid  that  the  bowel  becomes  distended  and 
evacuates  its  contents.  If,  however,  from  any  cause  this  fails  to  occur, 
a  gradual  absorption  follows  and  the  whole  of  the  salt  and  fluid  in  the 
bowel  is  absorbed.  These  salts  may  fail  to  purge,  for  example,  when 
the  blood  and  tissues  contain  very  little  fluid,  as  in  animals  which  have 
been  deprived  of  water  for  several  days  previously.  In  this  case  the 
osmotic  pressure  in  the  bowel  is  unable  to  draw  fluid  from  the  concen- 
trated blood,  which  on  the  other  hand  has  a  higher  attraction  for  the 
fluid  in  the  bowel  than  usual.  But  where  large  quantities  of  fluid  are 
present  in  the  tissues,  as  in  oedema  and  dropsy,  the  saline  cathartics 
drain  them  through  the  blood  into  the  bowel,  and  very  profuse  evacu- 
ation occurs,  with  the  disappearance  of  the  exudate. 

There  is  still  some  doubt  as  to  why  the  saline  cathartics  are  so  slowly 
absorbed  from  the  intestines,  but  the  most  widely  accepted  view  is  that 
they  fail  to  penetrate  into  the  cell,  exactly  as  the  salts  of  the  metals  fail  to 
penetrate  the  red  blood  cells,  that  there  is  a  distinct  affinity  between  the 
bowel  epithelium  and  the  chloride  of  sodium,  but  only  a  much  weaker  one 
between  it  and  the  cathartics,  which  therefore  fail  to  permeate  it.  The 
acceptance  of  this  view  does  not  involve  the  rejection  of  the  belief  that 
the  cell  is  actively  engaged  in  absorption,  for  it  is  difficult  to  explain 
how  a  solution  after  penetrating  the  superficial  layers  of  the  epithelium 
is  passed  on  from  them  to  the  blood  except  by  assuming  that  the  cell 
exercises  some  propelling  force,  which  maybe  exerted  only  during  its  life. 

The  further  question  arises,  why  the  intestinal  epithelium  should  be 
permeable  by  certain  salts  such  as  the  chloride  of  sodium  and  imper- 
meable by  others  (sulphate  of  sodium).  In  this  relation  it  has  been 
found  by  Hofmeister  and  Pauli  that  the  purgative  salts  have  a  greater 
tendency  to  precipitate  proteids  and  have  less  tendency  to  permeate  into 
unorganized  colloids  than  most  of  the  non-purgative  salts.  In  numer- 
ous other  instances  the  sulphates,  tartrates,  and  other  cathartic  anions 
have  proved  slower  in  permeating  into  living  cells  than  the  chlorides 


534  INORGANIC  SALTS,  ACIDS  AND  BASES. 

and  bromides,  and  their  effects  on  the  blood  cells,  muscle,  nerve,  and 
some  other  tissues  show  marked  deviations  from  those  of  the  halogen 
salts.  It  is  impossible  to  determine  at  present  how  far  the  action  of 
these  anions  is  explained  by  their  slow  permeation  and  how  far  a  more 
specific  action  is  involved,  but  there  can  be  no  question  that  the  former 
factor  is  the  predominant  one  in  many  of  these  reactions.  Another 
curious  relation  between  the  purgative  anions  is  that  their  calcium 
salts  are  all  very  much  less  soluble  than  those  of  the  salts  which  pene- 
trate the  epithelium,  but  whether  this  is  merely  a  coincidence  or  not  is 
uncertain.  Most  of  the  cathartic  anions  are  '  bivalent  or  trivalent,  but 
this  is  not  true  for  all  of  them,  for  the  higher  members  of  the  acetate 
series  are  absorbed  with  the  greatest  difficulty  by  the  intestine. 

The  saline  cathartics  induce  certain  changes  in  the  Blood  indirectly 
through  their  action  on  the  intestine.  They  prevent  the  absorption  of 
the  fluid  of  the  food,  or,  if  in  sufficient  concentration,  actually  draw 
fluid  from  the  blood  and  tissues  into  the  bowel,  and  under  both  condi- 
tions the  blood  becomes  more  concentrated  than  usual ;  in  the  first 
case  because  it  is  not  reinforced  by  the  usual  amount  of  fluid  from  the 
food,  in  the  second  because  it  actually  loses  fluid  into  the  intestine. 
This  concentration  of  the  blood  leads  to  a  sensation  of  thirst,  and  to  a 
lessened  excretion  of  fluid  by  the  kidneys  and  other  glands. 

A  certain  amount  of  salt  and  of  fluid  is  absorbed  from  the  intestine, 
unless  purgation  follows  very  rapidly,  and  this  salt  acts  in  the  blood 
and  tissues  in  the  same  way  as  the  salts  which  do  not  act  as  cathartics. 
When  very  dilute  solutions  of  these  salts  are  given,  therefore,  the  effect 
is  similar  to  that  of  ordinary  salt,  except  that  the  hydrsemia  and  the 
diuresis  do  not  follow  so  soon,  because  the  absorption  is  somewhat 
slower.  Stronger  cathartic  solutions  at  first  cause  a  concentration  of 
the  blood  and  lessened  urine,  but  afterwards  the  excess  of  salt  in  the 
blood  may  cause  diuresis.  The  greater  the  purgative  action,  the  less 
the  diuretic,  because  more  fluid  and  more  of  the  cathartics  are  thrown 
out  in  the  stools.  If  no  purgation  follows  for  any  reason,  as  when  the 
blood  has  been  concentrated  by  long  abstinence  from  water,  the  whole 
of  the  salt  eventually  passes  into  the  blood  and  is  excreted  by  the  kid- 
ney, and  may  cause  very  considerable  diuresis  and  a  still  further  con- 
centration of  the  blood.  The  sulphates  are  absorbed  by  the  epithelium 
of  the  renal  tubules  with  much  greater  difficulty  than  chloride,  and 
thus  offer  osmotic  resistance  to  the  absorption  of  the  fluid  in  the  tubules  ; 
sulphates  absorbed  into  the  blood  therefore  induce  a  more  diffuse  diuresis 
than  an  equal  amount  of  chloride,  but  less  of  the  former  reaches  the 
blood  generally,  so  that  the  chlorides  are  better  practical  diuretics. 

From  the  above  it  can  be  at  once  inferred  that  a  saline  cathartic  in- 
jected intravenously  causes  no  purgation,  for  instead  of  preventing  the 
passage  of  fluid  from  the  bowel  into  the  blood,  it  rather  encourages  its 
absorption  by  increasing  the  osmotic  pressure  of  the  blood.  And  this 
has  been  shown  to  be  the  case  by  repeated  experiment.  One  fact  which 
seems  to  be  opposed  to  this  explanation  is  that  the  saline  cathartics 
sometimes  cause  purgation  when  injected  in  very  small  quantity  into 


SALINE  CATHARTICS.  535 

the  subcutaneous  tissues  of  the  abdomen.  But  this  is  due  not  to  the 
specific  action  of  the  drug,  but  to  its  causing  pain  and  inflammation, 
and  in  fact  acting  as  a  counter-irritant  (Hay). 

The  statement  is  sometimes  made  that  the  saline  cathartics  act  as 
cholagogues,  i.  e.,  increase  the  secretion  of  bile,  but  this  has  been  shown 
to  be  erroneous  by  a  series  of  careful  observations. 

The  Temperature  is  often  somewhat  reduced  by  the  action  of  the 
saline  cathartics,  but  seldom  more  than  one  half  degree. 

The  habitual  use  of  saline  cathartics  is  often  efficient  in  Reducing 
the  Weight  in  obesity,  and  many  of  the  natural  mineral  waters  have 
a  considerable  reputation  in  the  treatment  of  such  cases.  The  way  in 
which  they  act  is  not  understood,  for  though  there  is  often  somewhat 
less  proteid  and  fat  absorbed  from  the  intestine,  this  appears  too  small 
to  account  for  the  loss  in  weight.  There  seems  no  reason  to  suppose 
that  any  marked  change  in  the  nitrogenous  metabolism  is  induced  by 
the  cathartics,  for  the  nitrogen  in  the  urine  is  often  practically  unal- 
tered in  amount.  The  only  remaining  explanation  of  the  efficiency  of 
these  salts  in  obesity  is  that  they  increase  the  oxidation  of  the  fats  of  the 
body,  presumably  by  altering  the  movements  of  the  body  fluids.  This, 
however,  is  only  a  surmise  which  as  yet  is  unsupported  by  known  facts. 

When  purgation  follows  the  administration  of  a  saline  cathartic, 
the  most  of  the  salt  escapes  in  the  faeces,  never  having  been  absorbed 
at  all.  When  the  salt  fails  to  purge,  however,  and  is  absorbed,  it 
undergoes  the  usual  exchanges  in  the  tissues  and  is  excreted  by  the 
urine.  There  is  no  reason  to  suppose  that  any  of  it  appears  again  in 
the  stomach  or  intestine. 

The  Sulphates  seem  to  pass  through  the  tissues  without  injuring  them, 
and  but  little  effect  is  observed  from  injecting  considerable  quantities  into 
the  blood.  When  the  sulphate  ion  is  combined  with  a  poisonous  base  such 
as  potassium  oT  magnesium,  the  injection  is  of  course  followed  by  character- 
istic symptoms;  but  the  anion  seems  to  be  comparatively  harmless. 

The  Phosphates  are  also  very  inactive  after  absorption.  Garngee  found  the 
orthophosphate  quite  harmless,  while  the  metaphosphates  and  pyrophosphatea 
are  poisonous,  more  especially  the  last,  when  injected  subcutaneously  or  intra- 
venously. Phosphates  absorbed  in  man  and  in  the  carnivora  are  excreted  by  the 
kidney  and  increase  the  acidity  of  the  urine  ;  in  the  herbivora  they  are  excreted 
exclusively  by  the  bowel  wall. 

The  Citrates  are  rapidly  oxidized  in  the  tissues  to  carbonates,  and  only 
traces  of  the  unchanged  salt  escape  in  the  urine.  The  urine  may  thus  be 
rendered  alkaline  by  the  administration  of  the  citrates,  especially  in  small 
quantities  which  are  insufficient  to  induce  purgation  (see  hydrates  and  car- 
bonates of  the  alkalies,  page  544).  The  Tartrates  are  more  slowly  oxidized, 
and  a  considerable  quantity  is  excreted  in  the  urine  unchanged.1  Injected 
into  the  blood  directly,  the  citrates  and  tartrates  seem  to  act  as  heart  poisons, 
but  very  little  is  known  in 'regard  to  this  point. 

The  Magnesium  Salts  first  accelerate  and  then  weaken  and  paralyze  the 
heart  and  depress  the  central  nervous  system,  when  they  are  injected  into 
the  blood,  but  induce  no  symptoms  when  they  are  absorbed  from  the  intes- 
tine, as  they  are  probably  rapidly  excreted  by  the  kidneys.  The  magnesium 
of  the  urine  is  certainly  increased  by  the  administration  of  the  salts  by  the 
mouth,  especially  if  they  fail  to  purge,  but  it  is  possible  that  some  of  the  mag- 
nesium is  excreted  by  the  bowel,  and  it  has  been  recently  suggested  that  it 


536  INORGANIC  SALTS,   ACIDS  AND  BASES. 

may  appear  in  the  milk.  In  the  frog  the  salts  of  magnesium  are  said  to 
paralyze  the  striated  muscles  in  the  same  way  as  those  of  potassium,  but 
no  such  effect  is  induced  in  mammals  even  by  intravenous  injection,  the 
animal  dying  from  the  action  on  the  heart  and  nervous  system  before  the 
muscular  action  is  elicited. 

The  oxide  and  carbonate  of  magnesium  differ  from  the  other  saline 
cathartics  in  being  very  insoluble  and  in  possessing  an  alkaline  reac- 
tion. Part  of  that  ingested  is  formed  into  magnesium  chloride  in  the 
stomach,  however,  and  the  carbonic  acid  present  in  the  intestine  may 
dissolve  part  by  forming  the  bicarbonate.  Their  alkalinity  serves  to 
remedy  any  excessive  acidity  of  the  stomach  or  intestine,  while  at  the 
same  time  they  are  mildly  cathartic.  (See  page  541.)  The  prolonged 
use  of  large  quantities  of  magnesia  has  in  some  cases  led  to  the  forma- 
tion of  large  concretions  in  the  bowel,  resulting  in  obstruction, 

PREPARATIONS. 

SODII  SULPHAS  (U.  S.  P.,  B.  P.),  Glauber's  salt  (Na2SO4,  10H2O),  soluble 
in  about  3  parts  of  cold  water,  2-30  G.  (30  grs.-l  oz.). 

MAGNESII  SULPHAS  (U.  S.  P.,  B.  P.),  Epsom  salts  (MgSO4,7H2O),  soluble 
in  H  parts  of  cold  water,  2-30  G.  (30  grs.-l  oz.). 

Potassii  Sulphas  (U.  S.  P.,  B.  P.),  1-4  G.  (15-60  grs.). 

These  are  crystalline  salts  with  a  harsh,  bitter  taste. 

SODII  PHOSPHAS  (U.  S.  P.,  B.  P.)  (Na2HPO4  +  12H,O),  soluble  in  about  6 
parts  of  cold  water,  1-30  G.  (15  grs.-l  oz.). 

Sodii  Pyrophosphas  (U.  S.  P.)  (Na4P2O7  +  10H2O),  1-20  G.  (15-300  grs.). 

These  are  crystalline  salts  with  a  cool,  saline  taste. 

Liquor  Sodii  Phosphatis  Compositus  (U.  S.  P.)  contains  sodium  nitrate  and 
citric  acid.  Dose,  8  c.c.  (2  fl.  drs.). 

Sodii  Phosphas  Exsiccatus  (U.  S.  P.),  dried  sodium  phosphate,  1  G.  (15  grs.). 

Potassii  Bitartras  (U.  S.  P.),  Potassii  Tartras  Acidus  (B.  P.),  cream  of  tartar 
(KHC4H4O6),  1-4  G.  (15-60  grs.). 

POTASSII  ET  SODII  TAB/TEAS  (U.  S.  P.),  SODA  TARTARATA  (B.  P.),  Rochelle 
salt  (KNaC4H4O6  +  4H2O),  soluble  in  1.4  parts  of  cold  water,  8-16  G.  (120- 
240  grs.). 

Potassii  Tartras  (B.  P.)  ((CHOH)2(COOK)2H2O),  30-240  grs. 

Potassii  Citras  (U.  S.  P.,  B.  P.)  (C3H4OH(COOK)3),  1-3  G.  (15-45  grs.). 

Lithii  Citras  (U.  S.  P.,  B.  P.)  (C3H4OH(COOLi)34H2O),  0.3-0.6  G.  (5- 
10  grs.). 

Sodii  Citras  (U.  S.  P.)  (2C3H4OH(COONa)8-f  11H2O),  1-3  G.  (15-45  grs.). 

These  form  salts  with  a  cool  saline,  or,  in  the  case  of  the  bitartrate,  acidulous 
taste.  They  are  all  very  soluble  in  water,  except  the  bitartrate.  The  citrates 
are  not  purgative  in  the  dose  given. 

MAGNESII  OXIDUM  (U.  S.  P.),  MAGNESIA  LEVIS  (B.  P.),  light  or  calcined 
magnesia  (MgO). 

MAGNESIA  PONDEROSA  (B.  P.),  MAGNESII  OXIDUM  PONDEROSUM  (U.  S.  P.), 
heavy  magnesia  (MgO). 

MAGNESII  CARBONAS  (U.  S.  P.)  ((MgCO3)4Mg(QH)2  +  5H2O). 

MAGNESII  CARBONAS  LEVIS  (B.  P.)  )  rafMeCO  ^   MirfOm    4H  O) 

MAGNESII  CARBONAS  PONDEROSA  (B.  P.) )  (l  M«°us)'  MStu 

These  all  form  white  amorphous  powders  with  an  earthy,  not  saline,  taste. 
They  are  insoluble  in  water,  but  the  carbonate  is  dissolved  by  excess  of  car- 
bonic acid.  0.3-4  G.  (5-60  grs.V 

Liquor  Magnesii  Carbonatis  (B.  P.),  fluid  magnesia,  contains  2  per  cent, 
of  carbonate  of  magnesia  dissolved  by  the  presence  of  carbonic  acid.  1-2 
fl.  oz. 


SALINE  CATHARTICS.  537 

Effervescing  Preparations. 

PULVIS  EFFERVESCENS  COMPOSITUS  (U.  S.  P.),  PULVIS  SOD.E  TARTARAT^; 
EFFEBVESCENS  (B.  P.),  Seidlitz  powder. 

This  powder  is  made  up  in  two  papers,  of  which  the  blue  one  contains  a 
mixture  of  3  parts  of  Rochelle  salt  and  one  part  of  sodium  bicarbonate,  in  all 
10.4  G.  (160  grs.),  while  the  white  paper  contains  2.25  G.  (38  grs.  B.  P.)  of 
tartaric  acid.  When  the  powders  are  dissolved  separately  in  water  and  the 
solutions  mixed,  the  tartaric  acid  acting  on  the  bicarbonate  releases  carbonic 
acid  with  effervescence. 

Liquor  Magnesii  Citratis  (U.  S,  P.)  is  a  solution  of  magnesium  citrate  with 
excess  of  citric  acid  to  which  potassium  bicarbonate  is  added.  The  whole  is 
bottled  tightly  and  effervesces  when  the  cork  is  removed.  150-400  c.c. 
(5-12  fl  oz.). 

Lithii  Citras  Effervescens  (U.  S.  P.,  B.  P.),  a  mixture  of  lithium  carbonate 
or  citrate  with  sodium  bicarbonate,  and  citric  acid  (and  tartaric  acid,  B.  P.). 
4-8  G.  (60-120  grs.). 

Magnesii  Sulphas  Effervescens  (B.  P.,  U.  S.  P.),  a  mixture  of  Epsom  salts, 
sodium  bicarbonate,  tartaric  and  citric  acids,  which  effervesces  when  mixed  with 
water.  60-240  grs.  for  repeated  administration  ;  for  a  single  administration 
£-1  oz. 

Sodii  Sulphas  Effervescens  (B.  P.),  a  similar  mixture  containing  the  sulphate 
of  soda  instead  of  that  of  magnesia.  60-120  grs.  for  repeated  administration  ; 
for  a  single  administration  |— J  oz. 

Sodii  Phosphas  Effervescens  (B.  P.,  U.  S.  P.),  similar  to  the  above,  but  con- 
taining the  phosphate  in  place  of  the  sulphate.  Dose  as  for  the  effervescent 
sulphate. 

Sodii  Citrotartras  Effervescens  (B.  P.),  a  mixture  of  sodium  bicarbonate 
with  tartaric  and  citric  acids.  It  is  not  purgative  in  the  dose  advised  in  the 
B.  P.  60-1 20  grs. 

Many  other  effervescent  mixtures  are  used  instead  of  the  official  ones — 
among  them  the  tartrates  and  citrates  of  the  alkalies,  the  acetate  of  mag- 
nesium, etc. 

The  sulphates  of  sodium  and  of  magnesium,  the  tartrates  of  sodium  and 
potassium  and  the  phosphate  of  soda  are  given  in  solution,  the  last  often  in 
milk.  Unless  under  special  conditions  the  salts  ought  not  to  be  in  greater 
concentration  than  5-10  per  cent.  Magnesia  and  magnesium  carbonate  are 
administered  in  powder,  sweetened  if  necessary.  The  effervescent  prepara- 
tions are  always  to  be  taken  in  solution  in  about  a  tumbler  of  water ;  in 
some  instances  in  which  this  was  not  understood,  severe  distention  of  the 
stomach  with  alarming  symptoms  have  arisen  from  the  carbonic  acid  being 
freed  in  the  stomach.  The  effervescent  preparations  ought  to  be  kept  dry, 
and  the  solution  of  magnesium  citrate  has  to  be  kept  tightly  corked. 

Very  often  the  natural  mineral  waters  are  used  instead  of  the  pharmaco- 
poeial  preparations,  the  best  known  purgatives  among  these  being  the  Hun- 
yadi-Janos  water  and  Carlsbad  water,  which  contain  the  sulphates  of  sodium 
and  magnesium.  "  Carlsbad  salts  "  are  obtained  by  the  evaporation  of  the 
waters,  but  are  very  often  artificial  imitations.  Many  other  springs  have 
the  same  effects,  and  a  widespread  belief  exists  that  the  natural  waters  are 
u  more  efficient  "  or  "  less  depressant "  or  have  some  mystical  virtues  that 
are  not  shared  in  by  the  artificial  salts,  but  this  belief  does  not  seem  to  have 
any  real  basis,  and  is  probably  a  survival  of  the  old  religious  belief  in  the 
healing  properties  of  springs. 

In  the  natural  waters  the  purgative  salts  are  always  accompanied  by  other 
less  active  ones,  such  as  the  chlorides  of  sodium,  calcium,  etc. 

The  sulphovinate  of  sodium  (N"aC.,H5SO4)  has  been  advised  as  an  aperient, 
but  is  much  weaker  than  the  others,  though  it  has  a  more  pleasant  taste. 
It  is  very  liable  to  decompose  with  the  formation  of  sulphate  of  soda,  and 
perhaps  much  of  its  action  may  be  due  to  the  presence  of  the  latter. 


538  INORGANIC  SALTS,  ACIDS  AND  BASES. 

Therapeutic  Uses. — The  saline  cathartic^  are  very  largely  used  to 
relieve  constipation.  Habitual  constipation  seems  to  be  caused  by 
insufficient  peristalsis,  and  the  slow  passage  of  the  contents  through  the 
intestines  allows  of  a  more  complete  absorption  than  usual,  this  in 
turn  rendering  the  faeces  hard  and  dry  and  difficult  to  move  onwards. 
The  saline  cathartics  increase  the  fluidity  of  the  intestinal  contents,  and 
thus  facilitate  their  expulsion,  and  this  is  probably  the  only  effect  they 
have  when  taken  in  small  quantities,  and  especially  in  dilute  solution 
as  in  the  natural  mineral  waters.  In  larger  quantities,  however,  more 
water  is  retained  in  the  bowel,  and  the  weight  and  distention  cause 
peristalsis,  while  in  sufficient  quantity  they  draw  fluid  from  the  blood 
and  cause  profuse  watery  discharges.  When  a  very  complete  evac- 
uation is  desired,  the  saline  cathartics  may  be  given  along  with  some 
of  the  vegetable  purgatives.  Such  mixtures  are  the  official  Black 
Draught  (see  Senna)  and  the  compound  powder  of  Jalap.  The  saline 
cathartics  act  much  more  rapidly  than  the  vegetable  purgatives,  and  a 
common  method  of  combining  their  effects  is  to  give  the  latter  in  the 
evening  and  the  saline  the  following  morning. 

The  chronic  constipation  due  to  sedentary  habits  is  much  benefited 
by  the  saline  cathartics,  more  especially  by  dilute  solutions  taken  be- 
fore breakfast.  The  sulphates  and  tartrates  are  harsh  and  unpleasant 
to  the  taste,  and  the  natural  waters  are  often  preferred,  or  one  of  the 
effervescent  preparations  may  be  used  in  those  cases. 

The  sulphates  and  tartrates  are  more  frequently  used  where  a  single 
large  dose  has  to  be  prescribed  in  order  to  empty  the  bowel,  but  here 
also  the  Seidlitz  powder  may  be  advised  instead,  as  being  more  agree- 
able to  the  taste.  These  cathartics  were  at  one  time  used  in  fever, 
partly  from  a  theory  that  they  reduced  the  temperature ;  they  are  cer- 
tainly less  liable  to  cause  pain  and  griping  than  the  vegetable  purga- 
tives, and  thus  tend  to  disturb  the  patient  less. 

The  sodium  phosphate  is  often  prescribed  for  children,  either  as  a 
powder  to  be  given  in  jelly,  or  in  solution  in  milk  or  other  food,  which 
completely  hides  its  taste. 

The  saline  cathartics  are  used  to  lessen  intestinal  putrefaction,  and 
are  sometimes  very  efficient,  though  they  do  not  act  through  any  an- 
tiseptic power,  but  simply  by  removing  the  putrefying  mass.  The 
phosphate  of  soda  has  been  especially  recommended  in  some  forms  of 
diarrhoea  in  children. 

The  saline  cathartics  are  administered  to  remove  accumulations  of 
fluid  in  the  body  arising  from  cardiac  or  renal  insufficiency,  or  from 
an  old  effusion.  For  this  purpose  the  sulphate  of  magnesium  is  used 
in  a  large  dose,  dissolved  in  about  its  own  weight  of  water ;  if  purgation 
does  not  follow  in  1-3  hours,  an  enema  may  be  necessary,  or  the  saline 
may  be  given  along  with  a  vegetable  purgative.  This  form  of  treatment 
was  very  popular  at  one  time,  but  is  liable  to  weaken  and  depress  the 
patient,  and  is  specially  contraindicated,  therefore,  in  asthenic  conditions. 
Other  methods  of  removing  accumulations  of  fluid  are  by  the  use  of 


SALINE  CATHARTICS.  539 

diuretics  (see  caffeine,  theobromine,  page  245),  diaphoretics  (see  pil(x 
carpine,  page  315),  or  by  cardiac  remedies  (digitalis,  page  440). 

As  diuretics  the  saline  cathartics  are  inferior  to  other  salts,  such  as 
the  acetates  or  nitrates.  Large  quantities  of  dilute  solutions  of  the 
purgative  salts  are  of  value  in  the  treatment  of  some  forms  of  obesity, 
the  mineral  waters  being  generally  prescribed  for  this  purpose,  or  the 
patient  being  sent  to  drink  them  at  their  source. 

Magnesia  and  magnesium  carbonate  are  less  liable  to  purge  than 
the  soluble  salts,  and  are  specially  indicated  in  hyperacidity  of  the 
stomach  or  in  acid  putrefaction  in  the  bowel.  They  cause  less  irrita- 
tion than  the  carbonates  of  the  alkalies  because  of  their  insolubility, 
and  at  the  same  time  have  the  advantage  of  acting  as  mild  purgatives, 
while  the  lime  preparations  which  are  insoluble,  tend  to  induce  con- 
stipation. The  magnesia  preparations  may  be  used  also  in  diarrhoea 
as  antacids,  as  they  have  no  irritant  action  on  the  bowel.  Freshly 
prepared  magnesia  is  recommended  in  arsenic  poisoning  to  form  an  in- 
soluble precipitate  in  the  stomach,  and  in  poisoning  with  acids  it  is 
also  of  value  when  it  can  be  obtained  readily.  In  both  cases  it  is  to 
be  given  in  large  quantities. 

The  phosphate  of  soda  has  been  given  in  various  bone  diseases,  as  in 
osteomalacia  and  rickets,  this  treatment  being  founded  on  the  belief  that 
the  softening  of  the  bones  is  due  to  the  lack  of  phosphates  in  the  food,  but 
there  is  no  reason  to  suppose  that  this  idea  is  correct,  and  the  treatment 
is  not  attended  with  success.  In  cases  of  exophthalmic  goitre  the  phosphate 
has  been  recommended,  but  no  explanation  has  been  given  of  its  action  here, 
and  some  question  exists  as  to  whether  it  is  really  of  value.1  It  has  also 
been  recommended  in  the  uric  acid  diathesis.  The  phosphates  have  been 
supposed  to  be  of  benefit  in  nervous  diseases,  on  the  theory  that  these  were 
due  to  the  insufficiency  of  phosphorus  in  the  brain,  and  glycero-phosphates 
have  been  introduced  for  the  same  reason,  but  both  theory  and  practice  have 
proved  to  be  erroneous,  for  the  animal  organism  is  unable  to  build  up  proteid 
combinations  from  their  inorganic  constituents.  The  use  of  sulphate  of 
sodium  in  phenol  poisoning,  which  was  at  one  time  recommended,  has  been 
shown  to  be  quite  without  effect  on  the  progress  of  the  intoxication.  (See 
Carbolic  Acid,  page  404.) 

The  ferrocyanide  of  potassium  has  been  advised  in  irritant  poisoning  with 
iron  and  copper  salts,  with  the  hope  that  the  insoluble  ferrocyanides  would 
be  formed ;  a  better  treatment,  however,  is  washing  out  the  stomach,  and 
the  greater  part  of  these  salts  is  removed  by  vomiting  in  any  case. 

BIBLIOGRAPHY. 

The  literature  of  saline  cathartics  up  to  1884  is  discussed  by  Hay.  See  also  Vege- 
table Purgatives,  p.  108,  and  Salt  Action,  pp.  489,  497. 

Hay.  Saline  cathartics,  Journ.  of  Anat.  andPhys.,  xvi.  and  xvii. ;  also  in  mono- 
graph, Edinburgh,  1884. 

London.     Zts.  f.  klin.  Med.,  xiii.,  p.  48. 

Dapper.     Ibid.,  xxx.,  p.  371.     Arch.  f.  Verdauungskrank.,  iii.,  p.  1. 

Jacoby.     Berl.  klin.  Woch.,  1897,  p.  248. 

Heidenhain.     Pfliiger's  Arch.,  IvL,  p.  579. 

K&vesi.     Centralbl.  f.  Physiol.,  1897,  p.  553. 

Hamburger.     Arch.  f.  Anat.  u.  Phys.,  1896,  p.  428. 

Hober.     Pfliiger's  Arch.,  Ixx.,  p.  624. 

Flemming.     Inaug.  Diss.,  Dorpat,  1893. 


540  INORGANIC  SALTS,  ACIDS  AND  BASES. 

Wallace  and  Cushny.  Am.  Journ.  of  Physiol.,  i.,  p.  411.  Pfliiger's  Arch.,  Ixxvii., 
p.  202. 

Gamgee,  Priedley  and  Larmuth.    Journ.  of  Anat.  and  Phys  ,  xi.,  p.  255.    (Phosphates.) 
Bergmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvii.,  p.  77. 
Swiatecki.     Ztschr.  f.  phys.  Chem.,  xv.,  p.  49. 

XIV.  HYDRATES  AND  CARBONATES  OF  THE  ALKALIES. 

The  hydrates  and  carbonates  of  potassium,  sodium  and  lithium  owe 
their  pharmacological  action  entirely  to  the  non -metallic  ion,  which 
is  so  much  more  powerful  than  the  metal  that  the  latter  may  be  dis- 
counted. In  the  hydrates  the  active  constituent,  then,  is  — HO. 
The  carbonates  and  bicarbonates  dissociate  into  K-  or  Na-  ions  and 
—  CO3,  but  the  latter  rapidly  combines  with  the  hydrogen  of  the  water 
and  thus  frees  —  OH,  so  that  the  final  effect  is  the  same  as  if  a  hydrate 
had  been  administered,  except  that  the  carbonates  are  less  rapidly  dis- 
sociated than  the  hydrates,  and,  less  — OH  being  formed,  are  less  violent 
in  their  action.  This  hydroxyl  ion,  then,  is  what  induces  the  alkaline 
reaction  of  the  solutions  and  their  pharmacological  effect,  the  metallic 
ion  only  serving  as  a  means  of  applying  the  hydroxyl  ion,  but  not 
affecting  the  pharmacological  action.  In  other  words  the  alkalinity 
(hydroxyl  ion)  of  the  hydrates  and  carbonates  determines  their  action  ; 
the  metal  has  no  practical  importance. 

It  is  therefore  erroneous  to  take  the  hydrates  and  carbonates  as  typifying 
the  action  of  potassium  or  sodium,  for  in  these  the  metallic  action  is  much 
less  distinct  than  in  the  chlorides,  the  Cl  ion  being  practically  inert,  while 
the  hydroxyl  is  exceedingly  poisonous. 

It  may  be  remarked  in  passing  that  the  importance  of  the  reaction  be- 
tween alkalies  and  acids  lies  not  in  the  combination  of  the  metal  with  the 
anion  of  the  acid,  but  in  the  combination  of  the  powerful  hydroxyl  ion  with 
the  hydrogen  ion  of  the  acid.  In  the  effects  of  potassic  hydrate  in  the 
stomach,  the  main  importance  is  to  be  attached  not  to  the  potassic  chloride 
formed  but  to  the  water  (K  —  HO  +  H  —  Cl  =  K  —  C1  +  H2O),  for  the  potas- 
sium and  chloride  ions  remain  unchanged  by  the  operation  while  the  hydroxyl 
and  the  hydrogen  ions  disappear. 

Action.  —  The  pharmacological  action  of  this  group  is  due  to  their 
powers  of  neutralizing  acids  and  of  dissolving  proteids  and  changing 
them  to  alkali-proteids,  and  in  a  less  degree  to  their  saponifying  fats. 
They  have  in  addition  the  ordinary  salt-action,  and  in  concentrated 
solutions  withdraw  fluid  from  the  tissues. 

The  solution  of  proteids  by  the  alkalies  and  the  characters  of  the 
compounds  thus  formed  outside  the  body  are  well  known  and  need  not 
be  entered  into  here.  The  same  solvent  action  is  observed  in  the  living 
tissues  whenever  the  hydrates  and  carbonates  come  in  contact  with 
them  in  sufficient  concentration.  The  hydrates  are,  of  course,  much 
more  powerful  solvents  than  the  carbonates,  and  these  than  the  bicar- 
bonates. In  very  dilute  solutions  this  solvent  action  is  exercised  only 
on  the  superficial  tissues,  but  when  stronger  solutions  are  used,  or 
when  even  weak  solutions  remain  long  in  contact  with  the  tissues, 
they  tend  to  penetrate  more  deeply  and  cause  widespread  destruction 
or  corrosion.  These  bodies  form  soluble  compounds  with  the  proteids 


HYDRATES  AND   CARBONATES   OF  THE  ALKALIES.         541 

and  are  only  slowly  neutralized  by  the  tissues,  so  that  no  such  bar- 
rier is  raised  against  their  penetration  as  is  met  by  some  other 
corrosives. 

Applied  to  the  Skin  weak  solutions  dissolve  the  superficial  layer  of 
horny  matter  and  the  oily  secretions  of  the  glands,  and  thus  cleanse 
the  surface  more  thoroughly  than  water  or  solutions  of  neutral  salts. 
When  applied  for  some  time,  they  penetrate  more  deeply  and  cause 
some  slight  irritation  and  redness.  Concentrated  solutions  dissolve 
the  skin  and  cause  necrosis  of  the  deeper  tissues,  generally  covered 
by  a  semitransparent  crust  which  falls  off  in  the  course  of  a  few 
days,  leaving  an  ulcer.  The  solutions  of  the  carbonates  are  much  less 
corrosive  than  those  of  the  hydrates,  and  induce  actual  lesion  of  the 
skin  only  under  exceptional  circumstances,  such  as  very  prolonged 
application. 

In  the  Mouth  the  hydrates  and  carbonates  have  a  characteristic 
"  alkaline  "  taste,  and  dissolve  the  superficial  layers  of  the  lining  mem- 
brane and  the  mucus  of  the  secretions.  The  lips,  tongue,  and  gums 
assume  a  bright  red  color  from  the  irritation  and  feel  soapy  to  the 
touch.  Concentrated  solutions  may  cause  deep  corrosion,  as  in  the 
skin,  while  very  weak  solutions  have  no  effect  except  the  characteristic 
taste  and  a  reflex  flow  of  saliva.  The  corrosion  caused  by  strong  solu- 
tions extends  to  the  throat  and  O3sophagus,  and  may  either  prove  im- 
mediately fatal  or  may  give  rise  to  cicatrices  subsequently. 

The  effect  of  the  hydrates  and  carbonates  in  the  Stomach  has  been 
much  disputed,  and  even  now  it  is  impossible  to  explain  some  of  the 
therapeutic  results.  Small  quantities  are  undoubtedly  neutralized  by 
the  hydrochloric  acid  of  the  gastric  juice  and  act  no  longer  from  their 
alkalinity,  but  merely  from  their  effects  as  salts,  if  at  all.  Larger 
quantities  render  the  contents  of  the  stomach  neutral  or  alkaline  and 
thus  prevent  gastric  digestion.  Very  concentrated  solutions  corrode 
the  walls  of  the  stomach  and  may  prove  immediately  fatal  from  caus- 
ing perforation  into  the  peritoneal  cavity,  while  if  the  corrosion  is  not 
so  severe,  and  the  patient  recovers  from  the  shock  and  collapse,  gastric 
ulcer  and  cicatrices  may  result. 

It  is  very  frequently  stated  that  alkalies  and  alkaline  carbonates  in- 
duce a  more  rapid  secretion  of  the  gastric  juice.  In  fact,  some  writers 
go  so  far  as  to  assert  that  it  is  impossible  to  render  the  contents  of  the 
stomach  alkaline  except  by  the  use  of  poisonous  doses,  because  the 
gastric  juice  is  so  rapidly  augmented  by  the  alkalies.  This  belief 
seems  to  be  founded  on  the  old  aphorism  contraria  contrariis  stimulan- 
tur}  which  proves  to  have  no  greater  basis  in  fact  than  other  similar 
dogmas.  It  has  been  demonstrated  experimentally  in  dogs  that  alka- 
line carbonates,  whether  given  by  the  mouth  or  injected  into  the 
stomach  through  a  gastric  fistula,  do  not  influence  the  amount  of  the 
gastric  secretion,  and  Reichmann  has  recently  shown  that  in  man  dis- 
tilled water  increases  the  free  acid  and  the  chlorides  of  the  stomach 
contents  as  much  as  an  equal  amount  of  an  alkaline  solution.  The 


542  INORGANIC  SALTS,   ACIDS  AND  BASES. 

only  satisfactory  examinations  of  the  question,  therefore,  show  that  the 
alkalies  have  no  effect  whatsoever  on  the  activity  of  the  secretory 
glands  of  the  stomach.  On  the  other  hand,  they  may  affect  the  juice 
already  secreted  by  making  it  neutral  or  even  alkaline,  and  may  thus 
render  it  entirely  useless  for  digestion  and  disinfection.  Of  course  in 
hyperacidity  of  the  stomach,  tlje  alkalies  may  be  of  benefit  by  lessen- 
ing the  amount  of  free  acid  present. 

Dilute  solutions  of  the  alkalies  may  act  as  slight  irritants  to  the 
stomach  wall  and  thus  improve  its  circulation,  and  lessen  pain,  eruc- 
tation and  distention,  very  much  in  the  same  way  as  other  slight  gas- 
tric irritants,  such  as  the  volatile  oils.  In  the  case  of  the  carbonates 
and  bicarbonates,  this  carminative  action  may  be  strengthened  by  the 
carbonic  acid  liberated  by  the  hydrochloric  acid.  In  addition,  they 
tend  to  render  the  mucus  less  tenacious,  or  may  dissolve  it  completely, 
and  thus  improve  the  condition  of  the  stomach.  Nothing  is  known  as 
to  their  effects  on  the  movements  of  the  stomach,  or  on  its  power  of 
absorption,  but  if  carbonic  acid  be  liberated,  it  tends  to  increase  the 
movements  to  some  extent. 

In  the  small  Intestine  the  alkalies  have  been  shown  to  have  an  in- 
direct effect,  through  their  diminishing  the  acidity  of  the  gastric  juice. 
The  secretion  of  the  pancreas  is  normally  stimulated  by  the  passage  of 
an  acid  fluid  through  the  pylorus,  and  if  the  acidity  of  this  fluid  be 
reduced  by  the  administration  of  alkalies,  a  much  smaller  quantity  of 
pancreatic  juice  is  thrown  into  the  intestine.  This  may  again  render 
the  digestion  less  complete,  although  the  greater  alkalinity  of  the 
intestinal  contents  tends  to  increase  the  efficiency  of  the  pancreatic 
juice  already  secreted.  On  the  other  hand,  in  cases  of  hyperacidity  of 
the  stomach,  the  administration  of  alkalies  may  render  the  contents  of 
the  intestine  less  irritant,  and  thus  tend  to  allay  catarrh. 

The  alkalies  administered  in  medicinal  doses  seem  to  have  no  effect 
on  the  intestinal  putrefaction,  for  the  double  sulphates  of  the  urine 
remain  unchanged  in  amount.  Kast  states  that  very  large  quantities 
(15  G.,  |  oz.)  increase  the  putrefaction,  probably  through  neutralizing 
the  disinfectant  gastric  juice. 

The  alkalies  have  been  believed  to  have  some  special  action  on  the 
Secretion  of  Bile ;  thus,  it  has  been  supposed  that  they  rendered  the 
bile  more  alkaline  and  tended  to  dissolve  the  mucus  contained  in  it, 
that  they  prevented  the  deposition  of,  and  even  dissolved  gall-stones, 
or  that  they  increased  the  secretion  of  bile  and  thus  swept  them  out  of 
the  gall-bladder.  All  of  those  theories  have  been  overthrown  by  the 
investigations  of  Stadelmann  and  his  pupils,  who  have  shown  that 
alkaline  salts  do  not  increase  the  secretion  of  bile,  are  not  excreted  in 
it,  and  do  not  cause  any  change  in  its  reaction.  Any  effect  which  the 
alkaline  carbonates  or  hydrates  may  possess  in  hepatic  diseases  would 
therefore  seem  due  to  their  effects  in  the  duodenum. 

The  prolonged  administration  of  very  large  doses  of  the  alkaline  car- 
bonates and  bicarbonates  causes  chronic  gastro-enteritis  in  animals, 
is  said  to  have  proved  fatal  to  them  in  some  instances, 


HYDRATES  AND   CARBONATES  OF  THE  ALKALIES.          543 

The  hydrates  are  probably  Absorbed  in  combination  with  proteids  or 
as  carbonates.  Both  hydrates  and  carbonates  disappear  rapidly  from 
the  stomach  and  intestine,  although  the  bicarbonate  of  soda  is  some- 
times credited  with  some  laxative  action  ;  this  may  not,  however,  be 
due  to  the  same  causes  as  in  the  case  of  the  saline  cathartics.  The 
absorption  of  these  bodies  leads  to  an  increase  in  the  alkalinity  of  the 
blood  and  tissues.  Even  when  the  alkali  administered  has  been  neu- 
tralized by  the  gastric  juice,  the  body  is  rendered  more  alkaline,  be- 
cause a  certain  amount  of  the  carbonate  of  the  blood  and  tissues  is 
spared,  which  would  normally  have  been  used  to  neutralize  the  hydro- 
chloric acid  before  it  could  be  reabsorbed.  This  condition  of  aug- 
mented alkalinity  can  only  last  a  short  time,  however,  as  the  excretory 
glands  at  once  proceed  to  remove  the  excess.  But  this  transient  in- 
crease in  the  alkalinity  of  the  tissues  has  been  supposed  to  influence 
the  Metabolism  very  considerably.  It  is  found  that  outside  the  body 
certain  bodies  undergo  oxidation  much  sooner  in  alkaline  solution 
than  when  neutral ;  the  example  most  frequently  cited  is  pyrogallol, 
which  combines  with  oxygen  much  more  rapidly  in  the  presence  of 
alkalies.  From  this  it  has  been  surmised  that  an  increase  in  the  alka- 
linity of  the  fluids  of  the  body  must  be  followed  by  an  acceleration  of 
the  metabolism.  A  large  number  of  researches  made  on  man  and  ani- 
mals in  regard  to  this  point  have  given  varying  results,  but  tend  on 
the  whole  to  show  that  the  alkalies  have  less  effect  on  the  tissue- 
change  than  was  formerly  believed.  The  investigators  of  the  subject 
have  generally  confined  their  attention  to  the  effects  of  alkalies  on  the 
products  of  metabolism  excreted  in  the  urine,  and  have  found  the  total 
nitrogen  excreted  to  be  unchanged  in  a  considerable  number  of  in- 
stances, to  be  slightly  increased  in  others,  and  to  be  diminished  in  a 
few  individuals.  Even  in  those  cases  in  which  an  increase  is  observed 
in  the  nitrogen  of  the  urine,  it  does  not  always  indicate  an  increase  in 
the  nitrogenous  metabolism,  for  the  urine  is  often  increased  consider- 
ably and  it  is  evident  that  the  interchange  of  the  fluids  of  the  tissues 
and  blood  is  augmented  ;  so  that  the  increased  nitrogen  of  the  urine  is 
accounted  for  by  the  tissues  being  more  thoroughly  flushed  out  than 
usual  by  the  alkalies,  which  act  in  the  same  way  as  the  neutral  salts. 
(See  page  494.)  The  effect  of  the  alkalies  on  the  total  nitrogen  ex- 
cretion seems  to  vary  considerably  with  the  individual,  and  in  one  and 
the  same  person  different  effects  have  been  noted  from  two  salts  which 
exist  in  the  blood  in  the  same  form. 

Although  the  total  nitrogen  may  be  little  affected  by  the  administra- 
tion of  the  alkalies,  the  form  in  which  it  is  combined  in  the  urine  and 
in  the  blood  may  be  changed.  The  ammonia  of  the  urine  is  often 
diminished  in  amount,  while  the  urea  excretion  is  correspondingly  aug- 
mented. This  is  especially  marked  in  cases  in  which  excess  of  acid  is 
formed  in  the  tissues  or  absorbed  in  any  way,  and  is  explained  by  the 
fact  that  this  acid  is  ordinarily  neutralized  by  the  formation  of  ammo- 
nia in  the  tissues  (see  Acids).  When,  however,  fixed  alkali  is  present 
in  sufficient  amount,  as  when  the  carbonates  are  given,  the  nitrogen 


544  INORGANIC  SALTS,   ACIDS  AND  BASES. 

which  would  otherwise  have  been  excreted  as  ammonium  salts,  is 
formed  into  urea. 

The  Uric  Acid  Excretion  under  the  alkalies  has  been  the  subject  of 
numerous  researches,  but  in  the  great  majority  of  these  very  imperfect 
methods  of  estimation  have  been  used.  In  the  few  cases  in  which 
satisfactory  methods  have  been  employed,  the  results  have  been  diver- 
gent, the  uric  acid  being  sometimes  decreased  and  sometimes  increased 
by  the  alkalies.  In  any  case  the  change  is  trifling  in  extent,  and  no 
inference  can  be  drawn  as  to  the  uric  acid  metabolism  from  it. 

As  regards  the  Oxidation  in  the  Tissues,  one  observer  found  the  oxy- 
gen absorbed  and  the  carbonic  acid  excreted  by  the  lungs  increased  by 
the  alkalies,  while  another  could  detect  no  change.  Another  method 
of  estimating  the  activity  of  the  oxidation  in  the  tissues  has  been  used 
by  Taniguti  and  Jawein,  who  both  found  that  in  man  the  neutral  sul- 
phur of  the  urine  is  increased  by  the  alkalies  at  the  expense  of  the 
acid  sulphates  ;  they  interpret  this  as  indicating  a  diminution  of  the 
oxidation  of  the  tissues.  On  the  other  hand,  Heifter  and  Harnack, 
using  the  same  method,  came  to  the  conclusion  that  the  oxidation  in 
the  tissues  of  the  dog  was  increased  by  the  alkalies,  and  this  accords 
with  Munk's  observation  that  a  diminution  of  the  alkalinity  of  the 
blood  of  the  horse  lessened  the  oxidation  of  phenol. 

The  only  conclusion  which  seems  admissible  from  these  laborious 
investigations,  is  that  the  tissue  waste  is  but  little  affected  in  amount 
by  the  increased  alkalinity  of  the  blood,  and  the  slight  changes  ob- 
served may  vary  not  only  in  different  species,  but  in  different  individ- 
uals, and  even  in  the  same  individual  at  different  times.  The  cause 
of  this  individual  variation  may  be  differences  in  the  amount  of  acid 
formed  in  the  tissues,  but  may  also  be  differences  in  the  local  effect  of 
the  alkalies  in  the  alimentary  tract. 

The  organism  rapidly  frees  itself  from  the  excess  of  alkali  by  Ex- 
creting alkaline  salts.  This  excretion  occurs  chiefly  in  the  urine, 
which  becomes  less  acid,  or  even  alkaline  in  reaction,  and  in  the  latter 
event  contains  bicarbonate  of  potash  or  soda.  As  a  general  rule,  the 
urine  soon  regains  its  acidity,  but  when  fairly  large  doses  are  given 
repeatedly,  its  action  may  be  kept  alkaline  constantly.  This  is  almost 
always  accomplished  in  man  by  the  administration  of  about  10—15  G. 
(160-240  grs.)  of  sodium  carbonate  in  24  hours,  but  some  persons 
require  a  still  larger  quantity,  while  others  require  much  less.  A  tem- 
porary alkaline  reaction  lasting  2-3  hours  may  often  be  induced  by  a 
single  dose  of  2-3  G.  The  alkalies  have  the  same  effect  on  the  excre- 
tion of  the  salts  in  the  urine  as  the  neutral  salts  —  large  doses  increase 
the  sodium,  potassium  and  chlorides  of  the  urine. 

The  injection  of  alkaline  carbonates  into  the  blood  induces  a  more  active 
secretion  from  the  bronchial  mucous  membrane,  according  to  Calvert,  while 
Rossbach  found  it  to  have  the  opposite  effect.  It  is  questionable  whether 
the  alkali  is  excreted  here. 

The  blood  of  rabbits  treated  with  alkalies  is  said  to  be  more  strongly  ger- 
micidal  than  usual,  and  these  animals  show  greater  resistance  to  infection 
with  anthrax  bacilli.  These  effects  are  not  due  to  the  increased  alkalinity 


HYDRATP:S  AND  CARBONATES  OF  THE  ALKALIES.       545 

of  the  blood  directly,  for  serum  is  not  rendered  more  bactericidal  when  alkali 
is  added  to  it  in  test-tube  experiments. 

When  dilute  alkaline  solutions  are  applied  to  Isolated  Organs,  they  gen- 
erally increase  their  activity  for  a  time,  but  subsequently  weaken  it,  while 
strong  solutions  are  immediately  poisonous.  Thus  the  ciliary  movement  of 
epithelium  is  accelerated  by  dilute  alkalies,  the  sodium  salts  acting  more 
strongly  than  the  potassium  because  of  the  poisonous  K-ion  of  the  latter. 
The  heart  also  contracts  longer  and  more  strongly  when  it  is  perfused 
by  a  chloride  of  sodium  solution  rendered  alkaline  by  carbonate  of  soda 
than  when  the  solution  is  neutral.  Somewhat  stronger  solutions  increase 
its  tonus  and  eventually  cause  systolic  standstill.  The  arteries  are  con- 
tracted in  the  same  way  by  contact  with  alkaline  solutions,  and  are  dilated 
when  acids  are  perfused  through  them.  Some  of  the  secretions  have  also 
been  found  to  be  increased  by  the  presence  of  alkalies,  thus  the  glands  of 
the  frog's  skin  are  stimulated  by  very  dilute  alkaline  solutions.  Loeb  has 
recently  observed  that  the  presence  of  the  —  OH  ion  causes  frog's  muscle 
to  absorb  considerable  quantities  of  water  from  a  dilute  salt  solution,  while 
on  the  other  hand  Hamburger  states  that  the  addition  of  small  quantities  of 
alkalies  to  the  drawn  blood  reduces  the  size  of  the  blood  cells.  Zoethout 
states  that  some  unicellular  organisms  prove  much  more  resistant  to  the 
effects  of  the  withdrawal  of  oxygen  when  they  are  placed  in  a  slightly  alka- 
line medium,  and  suggests  as  an  explanation  that  the  alkali  antagonizes 
some  poison  formed  during  asphyxia. 

Strong  alkaline  solutions  destroy  all  living  tissues  with  which  they  come 
in  contact. 

PREPARATIONS. 

POTASSII  HYDROXIDUM  (U.  S.  P.  ),  POTASSA  CAUSTICA  (B.  P.),  (KOH), 
potassium  hydrate,  caustic  potash — dry  white  pencils  or  fused  masses,  deliques- 
cent in  the  air  and  very  caustic. 

Sodii  Hydroxidum  (U.  S.  P.)  (NaOH),  sodium  hydrate  or  hydroxide,  caustic 
soda — white  translucent  pencils,  deliquescent  in  the  air,  and  very  caustic. 

Liquor  Potassii  Hydroxidi  (U.  S.  P.),  Liquor  Potasses  (B.  P.),  solution  of 
potassium  hydrate,  about  5  per  cent.,  0.6-2  c.c.  (10-30  mins.),  to  be  well 
diluted. 

Liquor  Sodii  Hydroxidi  (U.  S.  P.),  a  solution  of  sodium  hydrate  in  water, 
about  5  per  cent.,  1-4  c.c.  (15-60  mins.),  well  diluted. 

Liquor  Sodii  Ethylatis  (B.  P.),  an  18  per  cent,  solution  of  sodium  ethylate 
(C2H5ONa)  in  absolute  alcohol.  It  should  be  recently  prepared,  when  it 
forms  a  colorless  syrupy  liquid,  which  decomposes  in  the  presence -of  water, 
and  is  very  caustic. 

POTASSII  CARBONAS  (U.  S.  P.,  B.  P.)  (K2CO3),  a  white  granular  powder  of 
alkaline  reaction,  soluble  in  one  part  of  water.  0.5-3  G.  (5-30  grs.). 

SODII  CARBON  AS  (B.  P.)  (Na2CO3  +  10H2O),  colorless  crystals  with  an  alka- 
line reaction  and  taste,  soluble  in  about  one  part  of  water.  0.3-2  G.  (5-30  grs.). 

Sodii  Carbonas  Exsiccatus  (B.  P.),  sodium  carbonate  deprived  of  most  of  its 
water  of  crystallization,  a  loose,  white  powder  resembling  the  ordinary  carbonate 
in  its  reactions  and  solubility.  0.3-1  G.  (5-15  grs.). 

Sodii  Carbonas  Monohydmtus  (U.  S.  P.)  (Na2CO3  +  H2O),  a  white  crystalline 
powder  without  odor  and  strongly  alkaline.  Dose,  0.25  G.  (4  grs.). 

POTASSII  BICARBONAS  (U.  S.  P.,  B.  P.)  (KHCO3),  colorless,  transparent 
crystals  with  a  saline,  slightly  alkaline  taste  and  soluble  in  three  parts  of 
water.  0.5-2  G.  (10-30  grs.). 

SODII  BICARBONAS  (U.  S.  P.,  B.  P.)  (NaHCO3),  a  white,  opaque  powder, 
with  a  cool,  alkaline  taste,  soluble  in  11  parts  of  water  at  15°  C.  0.3-2  G. 
(5-30  grs.). 

Trochisci  Sodii  Bicarbonatis  (U.  S.  P.,  B.  P.). 

Sodium  bicarbonate  is  contained  in  the  Mistura  Rhei  et  Sodse  (U.  S.  P.). 
35 


546  INORGANIC  SALTS,  ACIDS  AND  BASES. 

Lithii  Carbonas  (U.  S.  P.,  B.  P.)  (Li2COs),  a  light,  white  powder  with  an 
alkaline  taste,  soluble  in  80  parts  of  water,  but  more  soluble  in  carbonic 
acid  water.  0.2-0.6  G.  (3-10  grs.). 

The  preparations  of  magnesia  and  magnesium  carbonate  (see  pp.  540-541) 
are  prescribed  more  as  antacids  than  as  cathartics,  and  might  be  included  in 
this  list. 

Numerous  alkaline  mineral  waters  are  used  instead  of  the  pharmacopoaial 
preparations,  but  as  a  general  rule  they  contain  only  very  small  quantities 
of  the  carbonates,  and  perhaps  act  more  through  the  large  amount  of  water 
than  through  their  alkaline  reaction. 

Therapeutic  Uses. — The  caustic  alkalies  are  used  Externally  to  a 
limited  extent  to  remove  growths  such  as  warts  from  the  skin.  For 
this  purpose  the  potash  pencils  are  employed,  but  they  are  very  de- 
liquescent and  it  is  therefore  difficult  to  limit  their  action  to  one  spot, 
and  to  the  superficial  tissues.  When  the  desired  extent  of  cauteriza- 
tion has  been  obtained,  the  part  should  be  washed  with  water,  or  with 
vinegar  or  some  other  dilute  acid.  The  solution  of  sodium  ethylate 
(B.  P.)  is  said  to  be  less  painful  than  caustic  potash.  The  carbonates 
are  also  used  externally  to  some  extent,  chiefly  in  baths,  which  they 
render  more  irritant  to  the  skin,  and  in  which  they  tend  to  soften  and 
remove  the  superficial  horny  layers  of  the  epithelium  more  than  ordi- 
nary water  or  solutions  of  the  neutral  salts.  The  carbonates  are  also 
applied  in  strong  solution  or  as  a  paste  in  itching  skin  diseases,  and 
often  give  relief. 

Internally  the  alkaline  carbonates  and  more  rarely  the  solutions  of 
the  hydrates  are  used  for  their  effect  on  the  stomach,  and  in  cases  of 
hyperacidity  relieve  the  pain  and  eructation  almost  instantly.  Even 
where  no  excessive  acidity  exists,  the  alkalies  are  often  beneficial  in 
small  quantities,  removing  the  distension  and  discomfort  without 
apparently  altering  the  digestion  to  any  marked  extent.  The  bicar- 
bonate of  potash  is  more  frequently  used  for  this  purpose  than  the 
others,  and  the  solutions  of  the  caustic  alkalies  are  comparatively  rarely 
employed.  Whatever  preparation  be  used,  it  ought  to  be  well  diluted 
to  avoid  the  irritant  action  on  the  stomach  wall.  Instead  of  these 
alkalies  the  carbonate  and  oxide  of  magnesium  may  be  employed  in 
powder,  and  possesses  the  advantage  of  not  causing  any  irritation  and 
at  the  same  time  have  some  aperient  action.  In  cases  of  hyperacidity 
the  alkalies  (antacids)  are  often  given  after  meals,  while  when  the 
secretion  does  not  seem  to  contain  an  excessive  amount  of  acid  they  are 
advised  before  meals,  and  may  then  be  combined  with  other  stomachics, 
such  as  bitters  or  volatile  oils. 

The  alkalies  are  also  administered  for  their  effects  after  absorption, 
and  here  the  bicarbonate  of  potash  is  most  frequently  prescribed, 
while  the  hydrate  solutions  are  rarely  used.1  Diabetes  was  formerly 
treated  in  this  way,  in  the  hope  that  the  oxidation  in  the  tissues  would 
be  increased,  but  there  is  little  reason  to  suppose  that  the  alkalies  have 
any  such  effect  on  the  metabolism,  and  it  is  now  generally  accepted 
that  diabetes  is  not  due  to  a  general  inability  of  the  tissues  to  oxidize. 

1  The  acetates,  citrates,  etc.,  may  also  be  used  for  this  purpose  (page  549). 


HYDRATES  AND   CARBONATES  OF  THE  ALKALIES.         547 

Experience  too  has  shown  that  the  glycosuria  is  not  lessened  appreci- 
ably by  the  use  of  the  alkalies.  When,  however,  diabetes  induces  an 
increased  acid  formation  in  the  tissues,  as  is  almost  invariably  the  case 
in  its  later  stages,  the  alkalies  are  of  undoubted  benefit  in  neutraliz- 
ing the  oxybutyric  acid  formed  and  thus  economizing  the  alkalies  of 
the  blood.  In  diabetic  coma,  temporary  improvement  may  very  often 
be  attained  by  the  use  of  large  doses  of  alkalies. 

In  gout,  rheumatism,  and  the  "  uric  acid  diathesis  "  generally,  the 
alkalies  have  been  used  very  extensively,  partly  in  the  hope  that  the 
supposed  increased  combustion  in  the  tissues  would  destroy  a  larger 
amount  of  the  uric  acid,  and  partly  with  the  idea  that  the  uric  acid 
being  neutralized  in  the  tissues,  would  be  excreted  more  easily  and 
would  have  less  tendency  to  be  deposited.  There  are  some  grounds  for 
believing  that  the  alkaline  carbonates  are  of  benefit  in  gout  and  rheu- 
matism, but  neither  of  these  theories  seems  sufficient  to  explain  their 
effects,  for  no  increase  in  the  oxidation  has  been  shown  to  occur,  and 
on  the  other  hand  the  uric  acid  is  not  believed  to  exist  in  either  the 
blood  or  the  urine  in  such  simple  combinations  as  the  urates.  In  the 
present  position  of  the  uric  acid  question  and  of  the  pathology  of 
these  diseases,  however,  it  is  futile  to  attempt  to  explain  their  thera- 
peutics, though  it  may  be  surmised  that  the  alkalies  may  influence  the 
formation  of  the  uric  acid  rather  than  its  excretion.  The  sodium  and 
potassium  salts  have  been  used  very  largely,  and  the  lithium  carbonate 
has  been  advised  on  the  ground  that  lithium  urate  is  about  four  times 
as  soluble  as  sodium  urate.  Lithium  has  also  been  administered  in 
the  form  of  the  benzoate  and  salicylate  in  these  diseases,  in  order  to 
combine  the  solvent  action  of  the  base  with  the  effects  of  these  acids, 
but,  as  in  so  many  other  similar  attempts,  one  of  the  chief  factors  in 
the  action  has  been  lost  sight  of;  much  too  small  quantities  of  the 
lithium  compounds  have  been  given  to  affect  the  reaction  of  the  blood, 
and  besides  the  salicylate  and  benzoate  do  not  alter  it  at  all,  as  they 
are  neutral  salts.  These  lithium  compounds  therefore  seem  to  be 
superfluous  in  the  treatment  of  these  diseases.  More  benefit  is  derived 
from  the  treatment  of  gout  and  rheumatism  by  the  alkaline  mineral 
waters  than  by  artificial  preparations,  and  this  is  especially  marked 
when  patients  are  sent  to  the  mineral  springs.  The  alkalinity  of  most 
of  the  waters  is  very  slight,  and  the  conclusion  is  inevitable  that  the 
curative  agency  is  not  the  alkalinity,  but  the  large  amount  of  fluid 
taken,  together  with  the  dietetic  and  other  hygienic  conditions. 

The  alkaline  preparations  are  also  largely  used  for  their  effects  in  the 
urine.  In  cases  of  excessive  acidity  of  the  urine  leading  to  pain  and 
straining  during  micturition,  the  symptoms  are  relieved  by  these  drugs 
rendering  the  fluid  less  irritating,  and  this  relief  is  especially  marked 
in  irritable  conditions  of  the  bladder  and  urethra.  They  may  also 
be  of  value  in  those  cases  by  rendering  the  mucus  more  soluble  in 
the  bladder.  In  gravel  the  alkalies  also  give  relief,  and  this  has  been 
attributed  to  their  dissolving  the  uric  acid  in  the  urine,  or  rather  to 
their  keeping  it  in  solution  in  the  form  of  salts.  In  order  to  attain 


548  INORGANIC  SALTS,  ACIDS  AND  BASES. 

this,  the  urine  would  have  to  be  rendered  alkaline,  or  at  least  neutral, 
and  relief  is  given  by  quantities  of  the  alkalies  which  are  quite  insuffi- 
cient to  do  this,  so  that  it  seems  more  probable  that  the  effects  are  due 
to  their  increasing  the  amount  of  the  urine,  and  thus  rendering  it  more 
dilute  than  to  their  actually  neutralizing  the  uric  acid.  Attempts  have 
even  been  made  to  dissolve  calculus  in  the  bladder  or  in  the  kidney  by 
treatment  with  the  alkalies,  but  there  is  no  question  that  this  is  hope- 
less. The  solution  of  the  alkalies  formed  in  the  urine  is  extremely 
dilute,  and  in  fact,  except  under  large  doses,  the  reaction  is  not  even 
constantly  neutral.  On  the  other  hand,  even  the  alkaline  urates  are 
by  no  means  very  soluble  bodies,  and  are  formed  only  with  difficulty 
except  in  strong  alkaline  solutions.  Again,  alkaline  urine  is  very  liable 
to  deposit  phosphates  in  the  bladder,  and  thus  rather  to  increase  the 
calculus  than  to  diminish  it.  Experience  has  shown  conclusively  that 
the  alkaline  treatment  does  not  remove  calculus,  although  in  one  or 
two  cases  it  is  stated  that  soft  calculi  broke  down  into  fragments  under 
it,  from  the  mucus  which  held  the  fragments  together  being  dissolved. 
The  pain  and  irritation  of  calculus  may  be  relieved  to  some  extent, 
however,  from  the  acidity  of  the  urine  being  lessened. 

The  alkaline  carbonates  are  also  prescribed  in  cases  of  jaundice  and 
gall-stone,  often  with  benefit.  This  is  not  due  to  their  acting  on  the 
bile  directly  in  all  probability,  for  it  has  been  shown  that  they  do  not 
affect  it  in  the  normal  animal  ;  the  improvement  may  rather  be 
ascribed  to  their  lessening  duodenal  irritation. 

Sodium  chloride  solution  is  often  injected  intravenously  in  shock 
and  heart  failure,  and  it  is  found  beneficial  to  add  a  small  quantity  of 
sodium  bicarbonate  (1  :  10,000)  to  it.  Alkaline  solutions  should  not  be 
injected  hypodermically,  as  sloughing  has  been  observed  repeatedly 
from  this  procedure. 

The  bicarbonate  of  potash  is  often  added  to  other  expectorant  reme- 
dies in  the  treatment  of  bronchial  catarrh  and  bronchitis,  and  is  be- 
lieved to  increase  the  secretion  and  render  it  more  fluid  and  more 
easily  expectorated. 

The  alkaline  carbonates  may  be  given  as  antidotes  in  poisoning  with 
the  corrosive  acids,  although  magnesia  is  preferable,  because  it  is  less 
irritating  to  the  stomach. 

In  cases  of  Poisoning  with  the  caustic  alkalies,  the  treatment  con- 
sists in  the  administration  of  dilute  acids,  of  which  the  organic  —  acetic, 
citric  or  tartaric  —  are  the  best.  The  first  is  most  readily  obtained  in 
the  form  of  vinegar.  No  attempt  should  be  made  to  pass  the  stomach 
tube,  as  it  is  liable  to  pass  through  the  corroded  wall  of  the  oesophagus 
or  stomach.  General  measures,  such  as  central  nervous  stimulants, 
warmth,  etc.,  may  be  taken. 

BIBLIOGRAPHY. 


Reichmann.     Arch.  f.  Verdauungskrankheiten,  i.,  p.  44. 
Kkigine.     Arch,  des  Scienc.  biologiques,  iii.,  p.  461. 
Becker.     Ibid.,  ii.,  p.  433. 


Glass.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxx.,  p.  241. 
Salfcowskiu.  Spilker.     Virchow's  Arch.,  cxvii.,  p.  570. 


HYDRATES  AND  CARBONATES  OF  THE  ALKALIES.         549 

Taniguti.     Ibid.,  cxvii.,  p.  581. 

Horbaczewski.     Monatsh.  f.  Chem.,  xii.,  p.  269. 

Freudberg.     Virchow's  Arch.,  cxxv.,  p.  566. 

Staddmann.     Einfluss  der  Alkalien  auf  den  menschlichen  Stoffwechsel,  1890. 

Jawein.     Ztschr.  f.  klin.  Med.,  xxii.,  p.  43. 

Hegeler.     Arch.  f.  Hyg.,  xl.,  p.  375. 

Culvert.     Journ.  of  Phys.,  xx.,  p.  158. 

Passcdsky  u.  Cruszewit*ch.     Maly's  Jahresber.,  xxiii.  (1893),  p.  427. 

Harnack  u.  Kkine.     Ztschr.  f.  BipL,  xxxvii.,  p.  417. 

Zoethout.     Amer.  Journ.  of  Physiol.,  ii.,  p.  220. 

Garrey.     Ibid.,  iii.,  p.  291. 

Piperazine  and  Quinic  Acid. 

Several  new  organic  compounds  have  been  introduced  of  late  years  as 
solvents  of  uric  acid  in  the  tissues  and  urine.  The  best  known  of  these  is 

/-ITT OTT 

piperazine  or  diethylendiamine   (NH<^pTT2     p,TT2^>NH)  ;   lycetol  and  lysidine 

are  nearly  related  bodies.  The  latest  remedy  is  quinic  acid,  C7H12O6,  which 
is  found  in  cinchona  bark  and  in  other  plants  ;  its  combinations  with  lithium 
citrate,  urotropine  and  piperazine  are  known  as  urosin,  chinotropine  and  sidonal. 
Piperazine  and  its  allies  dissolve  uric  acid  readily  in  the  test-tube,  much  more 
rapidly  than  lithium  or  borax,  which  are  often  prescribed  for  their  solvent  action; 
it  was  therefore  hoped  that  these  bases  would  prevent  the  deposit  of  uric  acid  in 
the  body  in  gout  by  forming  soluble  urates,  which  would  be  eliminated  in  the 
urine.  But  very  little  of  the  piper?zine  ingested  reappears  in  the  urine,  and  this 
quantity  is  too  small  to  have  any  solvent  action  on  the  uric  acid.  And  what 
does  escape  in  this  way  is  in  combination  with  the  stronger  acids  and  not 
with  the  uric  acid.  When  the  kidneys  are  inflamed  and  necrosed  in  birds 
through  the  action  of  chromic  acid,  the  uric  acid,  which  would  normally  be 
excreted  by  the  kidney,  is  deposited  in  various  organs,  but  this  does  not 
occur  except  in  the  kidney  if  piperazine  is  administered.  This  has  been 
used  as  an  argument  in  support  of  the  treatment  of  gout  with  piperazine, 
and  some  clinicians  have  had  very  favorable  results  from  it,  while  others 
have  been  disappointed.  It  is  said  to  relieve  the  discomfort  due  to  the  pas- 
sage of  gravel  in  some  cases,  while  failing  in  others,  but  it  has  not  been 
shown  to  be  of  any  value  in  the  treatment  of  calculus,  and  the  urine  of 
patients  treated  with  piperazine  has  no  more  solvent  action  on  uric  acid  than 
normal  urine.  Piperazine  seems  to  induce  no  symptoms  in  man  or  animals 
even  when  administered  in  large  quantities. 

Quinic  acid  has  been  suggested  as  a  treatment  for  gout  on  the  theory  that 
it  would  combine  with  glycocoll  in  the  body  and  thus  prevent  the  formation 
of  uric  acid,  a  theory  based  on  most  unsatisfactory  grounds.  As  a  matter 
of  fact  it  has  no  effect  whatever  on  the  amount  of  uric  acid  excreted.  In 
short  there  is  every  reason  to  believe  that  these  new  remedies  will  prove  no 
more  reliable  than  the  older  treatment  of  gout  and  the  "  uric  acid  diathesis." 

Piperazine  is  given  in  solution  in  doses  of  1  G.  (15  grs.). 

XV.     THE   ACETATE   SERIES. 

As  far  as  their  immediate  effects  are  concerned,  the  acetates  of  the  fixed 
alkalies  resemble  the  chlorides,  owing  any  effect  they  possess  to  the  salt- 
action.  In  the  tissues  however  the  acetates  are  oxidized  and  form  car- 
bonates, so  that  the  effects  are  those  of  the  chloride  before  absorption,  and 
those  of  the  carbonate  subsequently.  They  are  probably  partly  decomposed 
by  the  hydrochloric  acid  in  the  stomach,  and  in  the  intestine  they  are  rapidly 
absorbed.  The  oxidation  seems  to  proceed  rapidly,  and  is  very  complete, 
over  95  per  cent,  of  the  acetate  disappearing,  and  only  some  2-3  per  cent, 
being  excreted  unchanged  in  the  urine.  The  alkalinity  of  the  blood  and  of 


550  INORGANIC  SALTS,   ACIDS  AND  BASES. 

the  urine  is  increased  by  the  acetates  as  by  the  carbonates,  and  the  amount 
of  urine  is  increased. 

The  oxidation  of  the  acetates,  of  course,  supplies  energy  to  the  body  and 
they  are  therefore  foods  technically,  but  they  are  unable  to  replace  the  fats 
and  carbohydrates,  as  they  fail  to  lessen  the  nitrogenous  tissue  change  (com- 
pare alcohol,  p.  141).  Practically  they  are  useless  as  foods,  as  when  given 
in  sufficient  amount  they  derange  the  stomach  in  the  same  way  as  common 
salt  and  also  alter  the  character  and  amount  of  the  urine. 

The  acetates  seem  almost  devoid  of  specific  action — they  act  only  as  salts 
by  changing  the  physical  properties  of  the  body  fluids  or  as  alkalies  after 
absorption.  The  other  members  of  the  acetate  series  have  some  action,  how- 
ever, for  the  formate,  propionate,  butyrate  and  valerianate  of  soda  have  been 
shown  to  be  very  weak  narcotics  when  they  are  injected  hypodermically  or 
intravenously  ;  this  is  especially  marked  in  the  case  of  the  butyrate.  Rather 
more  of  the  formate  escapes  unchanged  in  the  urine  than  of  the  acetate, 
while  the  others  are  apparently  entirely  oxidized.  The  butyrate  differs  from 
the  acetate  in  being  capable  of  taking  the  place  of  the  carbohydrates  and 
fats  more  completely,  and  in  thus  leading  to  an  economy  of  the  nitrogenous 
tissues  of  the  body. 

All  of  the  simpler  salts  of  this  series  are  equally  rapidly  absorbed  from 
the  intestine,  but  the  cenanthylate  and  the  caprylate  resemble  the  saline 
cathartics  in  being  very  slowly  absorbed.  Probably  this  holds  also  for  the 
higher  members  of  the  acetic  acid  series,  including  the  salts  formed  by  the 
decomposition  of  fats — palmitates,  stearates,  etc. 

The  Lactates  resemble  the  acetates  in  being  almost  entirely  inactive,  but 
they  are  rather  more  slowly  absorbed  than  the  acetates.  They  are  oxidized 
in  the  tissues  for  the  most  part,  and  resemble  buty rates  in  limiting  the  nitro- 
genous waste,  at  any  rate  when  they  are  given  in  moderate  quantities. 
Lactic  acid  is  also  excreted  in  the  urine,  however,  in  considerable  quantity. 

PREPARATIONS. 

Potassii  Acetas  (IT.  S.  P.,  B.  P.),  a  crystalline  salt  of  pleasant,  saline  taste 
and  very  soluble  in  water.  1-4  G.  (15-60  grs.). 

Sodii  Acetas  (U.  S.  P.)  resembles  the  potassium  salt. 

Ammonii  Aceias.     (See  page  553.) 

Strontii  Lactas  (U.  S.  P.),  1-2  G.  (15-30  grs.). 

Acetate  of  potash  has  been  largely  used  as  a  diuretic  and  in  the  treatment 
of  gout  and  rheumatism.  It  acts  here  exactly  as  the  alkaline  carbonates  and 
bicarbonates,  but  has  the  advantage  of  not  neutralizing  the  gastric  juice,  or 
in  any  way  affecting  the  digestion  except  from  its  salt-action,  which  may  be 
minimized  by  exhibiting  it  in  dilute  solution. 

The  citrates  of  the  alkalies  may  be  used  for  the  same  purpose,  as  they  are 
not  cathartic  except  in  large  quantities.  (See  Saline  Cathartics,  p.  536.) 

BIBLIOGRAPHY. 

Buchheim.     Arch.  f.  phys.  Heilk.,  1857,  p.  122. 

Mayer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxi.,  p.  119. 

Weiskeu.  Flechsig.     Centralbl.  f.  Phys.,  1890,  p.  36. 

Mattevre.     Pfluger's  Arch.,  xlix.,  p.  460. 

Pohl     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi.,  p.  289  ;  xxxvii.,  p.  413. 


AMMONIA   AND   CARBONATE  OF  AMMONIA.  551 

XVI.     AMMONIA   AND    CARBONATE    OF   AMMONIA. 

Ammonia  solution  and  carbonate  of  ammonia  differ  considerably 
from  the  corresponding  hydrates  or  carbonates  of  the  fixed  alkalies  in 
their  effects.  The  gas  evaporates  rapidly  from  its  watery  solutions, 
and  the  carbonate  gives  off  ammonia  freely,  so  that  the  effects 
are  very  similar,  although  the  solution  of  ammonia  is  much  the  more 
powerful.  Owing  to  its  volatility,  ammonia  penetrates  more  rap- 
idly and  deeply  than  the  fixed  alkalies,  and  at  the  same  time  is  less  cor- 
rosive and  less  enduring  in  its  effects.  Applied  to  the  skin  in  concen- 
trated solution,  it  may  corrode  to  some  extent,  but  ordinary  dilute 
preparations  act  merely  as  rubefacients,  like  the  volatile  oils.  Even 
concentrated  solutions  do  not  dissolve  the  epidermis  like  the  fixed 
alkaline  hydrates,  but  tend  to  penetrate  through  it  and  raise  blisters. 
When  inhaled,  the  irritation  of  the  nasal  mucous  membrane  causes  a 
reflex  stimulation  of  the  vaso-motor  centre,  and  consequent  contrac- 
tion of  the  arterioles  and  augmented  blood-pressure,  while  the  respira- 
tion is  first  arrested,  and  then  becomes  deeper  and  fuller.  The  heart 
may  be  temporarily  slowed  by  inhibitory  reflexes.  Three  parts  of 
ammonia  in  10,000  of  air  cause  sneezing,  pain  in  the  nose,  and  tears, 
when  inspired  by  man,  and  5  parts  in  10,000  are  dangerous  when  in- 
haled for  some  time  (Lehmann).  Ammonia  is  not  absorbed  by  the 
lungs,  and  the  syniptoms  arise  only  from  the  local  irritation  and  subse- 
quent inflammation. 

Concentrated  solutions  cause  corrosion  of  the  mouth,  oesophagus  and 
stomach  similar  to  that  seen  in  poisoning  with  the  fixed  alkalies,  but 
some  of  the  vapor,  passing  into  the  respiratory  passages,  often  sets  up 
spasm  of  the  glottis,  or  such  swelling  of  the  mucous  membrane  of  the 
larynx  and  trachea  as  to  induce  asphyxia.  In  cases  of  ammonia 
poisoning,  therefore,  the  symptoms  often  arise,  not  so  much  from  the 
gastric  corrosion  as  from  asphyxia,  and  death  may  occur  very  suddenly 
from  this  cause,  The  carbonate  of  ammonia,when  swallowed,  also  causes 
slight  gastric  irritation,  and  in  larger  quantities  nausea  and  vomiting. 

After  absorption  ammonia  and  its  carbonate  are  rapidly  changed  to 
urea,  and  thus  differ  from  the  fixed  alkalies  in  not  rendering  the  blood 
more  alkaline,  and  in  having  no  effect  on  the  urine  except  to  increase 
the  urea  and  thereby  cause  some  diuresis. 

The  carbonate  of  ammonia  stimulates  the  central  nervous  system 
when  it  is  injected  into  the  blood  in  some  quantity,  but  it  is  very 
doubtful  whether  either  the  hydrate  or  the  carbonate  has  any  such 
effect  when  absorbed  from  the  stomach.  (Cf.  Ammonium  Chloride, 
page  496.) 

PREPARATIONS. 

Aqua  Ammonite  Fortior  (U.  S.  P.),  a  solution  of  ammonia  in  water,  con- 
taining 28  per  cent,  of  the  gas  by  weight. 

Liquor  Ammonite  Fortis  (B.  P.),  32£  per  cent,  by  weight. 

Aqua  Ammonite  (U.  S.  P.),  Liquor  Ammonia  (B.  P.),  an  aqueous  solution 
of  ammonia  of  10  per  cent,  strength  by  weight. 


552  INORGANIC  SALTS,  ACIDS  AND  BASES. 

Spiritus  Ammonice  (U.  S.  P.),  an  alcoholic  solution  of  ammonia  containing 
10  per  cent,  of  the  gas  by  weight.  1-2  c.c.  (15-30  mins.). 

SPIRITUS  AMMONITE  AROMATICUS  (U.  S.  P.,  B.  P.),  Aromatic  Spirit  of 
Hartshorn,  Spirit  of  Sal  Volatile,  contains  ammonia  and  ammonium  carbonate 
along  with  several  volatile  oils  dissolved  in  alcohol.  1-4  c.c.  (15-60  mins.), 
in  a  glass  of  water. 

Linimentum  Ammonias  (U.  S.  P.,  B.  P.),  ammonia  liniment,  volatile  lini- 
ment, contains  about  3.5  per  cent,  of  ammonia  (2.5  per  cent.  B.  P.). 

AMMONII  CARBONAS  (U.  S.  P.,  B.  P.)  is  not  the  pure  carbonate  but  a  mix- 
ture of  somewhat  varying  composition  consisting  of  carbonate  (NH4HCO3) 
and  carbamate  of  ammonia  (NH4NH2CO2).  It  releases  ammonia  in  the  air 
and  has  therefore  its  pungent  taste  and  smell.  It  forms  translucent,  crys- 
talline masses,  is  very  soluble  in  water  and  is  contained  in  the  aromatic 
spirit  of  ammonia.  0.2-0.6  G.  (3-10  grs.)  in  dilute  solution. 

Ammonia  is  contained  in  several  of  the  tinctures  of  the  B.  P.  (ammoniated 
tinctures)  and  in  the  Linimentum  Camphorse  Ammoniatum,  etc. 

Therapeutic  Uses.  —  The  aqueous  solutions  of  ammonia  are  compara- 
tively rarely  employed,  although  the  strong  solution  has  been  advised 
as  a  vesicant  in  cases  of  renal  disease,  in  which  cantharides  is  contra- 
indicated.  The  ammonia  solution  has  to  be  covered  by  a  watch-glass 
in  order  to  prevent  its  evaporation,  and  is  said  to  be  more  painful 
than  other  vesicants.  The  liniment  is  used  as  a  rubefacient  in  bruises 
and  in  other  similar  conditions.  The  gas  arising  from  ammonium 
carbonate  is  often  inhaled  in  cases  of  fainting  or  collapse,  in  order  to 
elicit  reflex  stimulation  of  the  medullary  centres.  The  ordinary 
"smelling  salts  "  used  for  this  purpose  consist  of  the  carbonate  reinforced 
with  some  of  the  strong  solution  and  flavored  with  oil  of  lavender. 

The  aromatic  spirits  of  ammonia  and  the  carbonate  (in  solution)  are 
used  as  mild  gastric  stimulants  in  debility,  flatulence  and  alcoholism, 
and  are  very  efficient  for  a  short  time.  Large  doses  of  the  carbonate 
(2  G.)  have  been  used  as  emetics,  and  are  less  depressant  than  many 
others,  such  as  tartar  emetic  or  ipecacuanha. 

The  carbonate  of  ammonia  and  the  spirits  or  even  the  ordinary 
water  of  ammonia  are  .often  given  in  cases  of  collapse  or  sudden  heart 
failure.  They  are  generally  administered  by  the  mouth  and  probably 
act  here  not  directly  on  the  heart  and  respiratory  centre,  as  has  been 
supposed,  but  reflexly  from  gastric  irritation.  They  have  also  been  in- 
jected subcutaneously  or  even  intravenously  for  this  purpose,  and  here 
the  local  action  may  be  reinforced  by  a  direct  action  on  the  medulla 
oblongata.  The  action  lasts  only  a  very  short  time,  but  is  often  suffi- 
cient to  tide  the  patient  over  an  acute  collapse.  In  depression  from 
many  different  causes  the  aromatic  spirits  of  ammonia  is  a  favorite 
remedy,  and  probably  owes  its  value  to  its  gastric  action,  and  not  to 
any  changes  in  the  central  nervous  system.  The  carbonate  is  often 
added  to  other  expectorant  remedies  to  render  the  bronchial  mucous 
secretion  more  fluid.  (See  Ammonium  Chloride,  page  496.) 

Strong  water  of  ammonia  is  applied  locally  in  snake-bite,  and  is 
popularly  believed  to  be  very  efficacious.  It  has  no  effect  on  the  tox- 
albumins  of  snake  poison,  and  probably  is  of  little  or  no  value  in  these 
cases. 


OXALATES.  553 

BIBLIOGRAPHY. 

See  Ammonium  Chloride,  page  496. 
Lehmann.     Arch.  f.   Hygiene,  v.,  p.  1. 

The  Acetate  of  Ammonia  acts  in  the  same  way  as  the  chloride 
locally,  but  undergoes  oxidation  in  the  tissues,  and  the  whole  is  changed 
to  urea,  so  that  the  ammonia  of  the  urine  is  not  increased,  but  only  the 
urea.  In  the  form  of  its  solution,  the  spirit  of  Mindererus,  it  is  used 
as  a  diaphoretic  and  diuretic,  and  is  often  prescribed  along  with  more 
powerful  remedies  in  fever. 

PREPARATIONS. 

Liquor  Ammonii  Acetatis  (U.  S.  P.,  B.  P.),  spirit  of  Mindererus,  contains 
about  7  per  cent,  of  the  acetate  with  some  free  acetic  acid  and  carbonic  acid 
and  must  be  freshly  prepared.  10-25  c.c.  (2-6  fl.  drs.). 

Liquor  Ammonii  Citratis  (B.  P.)  resembles  the  solution  of  the  acetate. 
2-6  fl.  drs. 

XVII.     OXALATES. 

The  oxalates  (NaOOC— COONa,  sodium  oxalate)  differ  from  the  acetate 
series  is  not  undergoing  oxidation  in  the  tissues,  and  in  being  poisonous  to 
most  forms  of  living  matter.  This  poisonous  action  is  shown  in  the  frog  by 
depression  and  final  paralysis  of  the  central  nervous  system,  the  brain  being 
first  affected,  then  the  medulla  oblongata  and  spinal  cord.  Later  still,  the 
terminations  of  the  peripheral  nerves  and  the  muscles  and  heart  are  para- 
lyzed, twitching  and  fibrillary  contractions  of  the  voluntary  muscles  often 
being  observed  first. 

In  mammals  there  is  apparently  at  first  a  stimulation  of  the  medullary 
centres,  for  rapid,  deep  breathing  occurs  in  the  rabbit,  and  vomiting  and 
nausea  in  the  dog,  and  according  to  some  observers,  the  arterial  tension  is 
first  increased  through  stimulation  of  the  vaso-motor  centre.  Later  the 
movements  are  wanting  in  coordination,  the  respiration  becomes  slow  and 
dyspnoeic,  the  heart  is  weak,  and  the  animal  becomes  comatose  and  dies, 
sometimes  in  convulsions. 

In  cases  of  oxalate  poisoning  in  man,  the  early  symptoms  are  great  mus- 
cular weakness,  twitching  of  the  muscles,  especially  of  those  of  the  face, 
more  rarely  convulsions  ;  later  there  follows  collapse  with  a  weak,  fluttering 
pulse,  pallor  or  cyanosis,  coma  and  death. 

Oxalates  are  very  poisonous  to  all  forms  of  animal  life  and  to  plants  con- 
taining chlorophyll,  but  are  harmless  to  the  moulds,  bacteria  and  some  alg£e. 
They  are  absorbed  with  great  difficulty  from  the  stomach  and  intestine,  and 
cause  irritation  and  effusion  of  liquid  except  in  very  dilute  solutions.  Added 
to  the  blood  outside  or  inside  the  body,  they  prevent  its  coagulation,  and  the 
rennet  ferment  also  fails  to  coagulate  milk  in  the  presence  of  small  quanti- 
ties of  oxalate  (see  Calcium).  The  frog's  heart  is  very  much  weakened  by 
the  addition  of  oxalate  of  soda  to  the  blood  perfused  through  it,  while  the 
mammalian  heart  is  not  affected  by  very  small  quantities,  but  if  the  injection 
of  oxalate  be  continued,  becomes  suddenly  weaker.  The  action  on  the  cen- 
tral nervous  system  has  been  mentioned  already,  and  consists  in  depression, 
which  is  sometimes  intermixed  with,  or  preceded  by  symptoms  of  stimulation. 

When  the  ordinary  nerve-muscle  preparation  is  soaked  in  oxalate  solution, 
the  same  twitching  and  tremor  of  the  muscle  is  observed  as  when  the  salt  is 
injected  into  the  frog.  Later  the  nerve  ends  are  paralyzed,  and  the  nerve 


554  INORGANIC  SALTS,  ACIDS  AND  BASES. 

fibres  lose  their  irritability,  as  is  indicated  by  the  disappearance  of  the  elec- 
trical current  of  action.  The  muscle  is  extremely  weak,  and  according  to 
several  observers,  loses  its  irritability,  while  Locke  finds  that  it  can  be  made 
to  contract  locally  by  strong  currents,  even  after  being  soaked  for  several 
hours.  The  post-mortem  rigor  does  not  seem  to  be  prevented  by  oxalate  as 
has  been  stated  by  some  observers. 

Oxalate  solutions  precipitate  lime  salts,  and  as  it  is  well  known  that  lime 
is  an  essential  constituent  of  living  matter,  it  has  been  suggested  that  the 
oxalates  cause  these  changes  in  the  organism  not  through  any  direct  action 
on  protoplasm,  but  through  their  precipitating  the  calcium  and  thus  chang- 
ing its  ordinary  relation  to  the  proteids.  This  explanation  has  been  sup- 
ported by  the  discovery  that  calcium  salts  added  after  oxalates  restore  the 
lost  function  in  many  cases,  although  this  of  course  admits  of  the  explana- 
tion that  the  calcium  merely  throws  the  oxalate  out  of  solution,  and  does  not 
really  supply  fresh  lime  to  the  tissues.  The  presumption  is  strong  however 
that  the  action  of  the  oxalates  is  due,  at  any  rate  in  part,  to  their  precipi- 
tating the  calcium  in  the  tissues,  although  they  may  have  a  specific  action 
on  living  matter  in  addition. 

The  alkalinity  of  the  blood  was  found  to  be  much  reduced  by  the  admin- 
istration of  neutral  oxalates  (Meyer),  and  it  has  been  surmised  that  this  is 
because  the  oxidation  of  the  tissues  is  retarded  by  the  presence  of  oxalates 
in  the  blood.  This  may  account  for  the  appearance  of  a  reducing  body  in 
the  urine  of  animals  poisoned  with  oxalate  ;  it  sometimes  occurs  in  poisoning 
in  man  and  is  said  not  to  be  dextrose. 

Practically  the  whole  of  the  oxalate  ingested  is  excreted  in  the  urine  in 
the  form  of  oxalate  of  calcium,  and  the  insoluble  crystals  are  often  deposited 
along  the  urinary  tubules  and  may  stop  them  up  entirely  and  thus  cause 
anuria,  congestion  and  inflammation  of  the  kidney  ;  albuminuria  is  often  the 
most  marked  symptom  in  slight  poisoning  in  man.  The  deposits  of  oxalates 
often  form  white  lines  running  from  the  base  to  the  apex  of  the  renal  pyra- 
mids, wrhich  are  quite  evident  macroscopically  at  the  autopsy.  Small  oxa- 
late calculi  have  also  been  produced  in  the  pelvis  of  the  kidney,  bladder, 
or  ureter  through  the  prolonged  administration  of  oxalate  or  oxamide  to 
animals.  Not  infrequently  these  renal  changes  are  the  only  lesioos  found 
post-mortem  in  cases  of  poisoning  with  oxalates. 

The  prolonged  administration  of  oxalates  to  animals  has  been  found  to 
induce  changes  in  the  skeleton,  for  sheep  fed  on  plants  containing  much  ox- 
alate, are  found  to  have  less  lime  in  the  bones  than  usual,  and  in  rabbits 
symptoms  of  rickets  are  said  to  be  induced  from  the  lessened  absorption  of 
lime. 

The  other  members  of  the  oxalate  series,  malonates  (CH2(COONa)2)  and 
succinates  ((CH2)2(COONa)2),  differ  from  the  oxalates  in  being  very  much 
less  poisonous,  the  fatal  dose  of  malonate  of  soda  being  about  twenty  times 
that  of  the  oxalate,  and  the  succinate  being  almost  indifferent.  The  malo- 
nate is  almost  completely  oxidized  in  the  tissues,  and  succinate  disappears 
completely.  It  is  significant  that  malonic  and  succinic  acids  form  much 
more  soluble  salts  with  lime  than  does  oxalic  acid.  Both  malonate  and  suc- 
cinate of  soda  are  absorbed  only  slowly  from  the  intestine,  and  act  as  saline 
cathartics. 

The  oxalates  are  not  used  in  therapeutics.  In  cases  of  oxalate  poisoning 
the  natural  antidote  is  lime,  which  forms  an  insoluble  precipitate  in  the 
stomach  and  may  also  relieve  the  symptoms  induced  by  the  withdrawal  of 
lime  from  its  normal  combination  in  the  tissues.  At  the  same  time  large 
quantities  of  water  and  diuretics  may  be  given  in  order  to  wash  out  the 
crystals  of  oxalate  from  the  urinary  tubules. 


ACIDS.  555 

BIBLIOGRAPHY. 

(See  Calcium.) 

Krohl     Arb.  a.  d.  pharm.  Inst.  zu  Dorpat,  vii.,  p.  130. 

Meyer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xvii.,  p.  304. 

Neubercjer.     Ibid.,  xxvii.,  p.  39. 

Oaglw.     Ibid.,  xxii.,  p.  246. 

Pohl    Ibid.,  xxxvii.,  p.  413. 

Ebstein  u.  Nicolaier.     Virchow's  Arch.,  cxlviii.,  p.  366. 

Ringer.     Practitioner,  xxxiv.,  1885,  p.  81. 

Locke.     Journ.  of  Phys.,  xv.,  p.  119  ;  xvii.,  p.  293. 

Hawaii.     Ibid.,  xvi.,  p.  476. 

Heymanns.     Arch.  f.  Anat.  u.  Phys.,  1889,  p.  168. 

Marfori.     Arch.  Ital.  de  Biol.,  xxvi.,  p.  194. 

Nathusius.     Centralbl.  f.  Phys.,  1897-98,  p.  608. 

Vietinghoff-Scheel.     Arch,  internat.  de  pharmacodyn. ,  viii.,  p.  225. 

XVIII.    ACIDS. 

Some  acids  owe  their  activity  in  the  organism  almost  entirely  to 
their  acidity,  i.  e.,  to  the  hydrogen  ion,  which  is  much  more  powerful 
than  the  potassium  ion,  but  otherwise  stands  on  the  same  plane  with 
it ;  those  acids  may  therefore  be  treated  of  together.  In  the  case  of 
many  other  acids  such  as  prussic  or  salicylic  acid,  the  effects  of  the 
acidity  or  hydrogen  ion  are  insignificant  in  comparison  with  those  of 
the  rest  of  the  molecule  or  the  negative  ion,  and  these  are  treated  along 
with  their  salts. 

Action.  —  The  acids  owe  their  action  on  living  tissues  to  their  neu- 
tralizing alkalies,  to  their  withdrawing  water,  when  in  concentrated 
form,  and  to  their  precipitating  some  of  the  proteids,  more  especially 
the  globulins. 

Most  living  matter  is  neutral  Or  slightly  alkaline  in  reaction,  and 
seems  to  be  incapable  of  existing  in  acid  media.  Exceptions  are  met 
with  in  some  of  the  moulds  and  in  other  vegetable  organisms  which 
live  in  somewhat  acid  solutions,  but  even  these  are  destroyed  by  more 
concentrated  solutions,  perhaps  because  the  acids  precipitate  their  pro- 
teids. Acids  are  therefore  Protoplasm  Poisons  and  antiseptics  of  some 
power.  Hydrochloric  acid  is  found  to  delay  the  growth  of  organisms, 
and  even  to  destroy  the  great  majority  of  the  less  resistant  forma  *n 
0.2-0.3  per  cent,  solution,  or  in  the  percentage  in  which  it  exists 
in  the  gastric  juice.  The  others  vary  in  strength  largely  according  to 
their  acidity,  that  is,  according  to  the  number  of  hydrogen  ions,  or 
the  amount  of  dissociation.  The  anion  has  also  some  effect  in  many 
cases. 

When  sulphuric  or  nitric  acid  is  applied  to  the  Skin  in  concentrated 
form,  it  acts  as  a  powerful  caustic,  destroying  the  epidermis  and  pene- 
trating to  some  distance  into  the  skin  and  subcutaneous  tissues,  in 
which  it  causes  necrosis.  This  is  of  course  accompanied  by  great 
pain,  and  if  much  of  the  skin  is  attacked,  by  shock  and  collapse  and 
symptoms  similar  to  those  seen  in  severe  burns.  Sulphuric  acid  causes 
a  white,  later  a  brown  or  black  eschar,  nitric  acid  a  yellow.  Hydro- 
chloric acid  is  less  liable  to  cause  wholesale  destruction  of  the  skin, 
but  penetrates  the  epidermis  and  raises  blisters.  The  organic  acids 


556  INORGANIC  SALTS,  ACIDS  AND  BASES. 

and  phosphoric  acid  are  still  less  irritant,  but  cause  redness  and  even 
blistering  when  applied  in  concentrated  solution.  Dilute  solutions  of 
the  acids  may  act  as  slight  irritants  to  the  skin,  and  often  cause  a  feel- 
ing of  stiffness  and  numbness,  perhaps  from  precipitating  the  proteids. 

The  corrosive  action  of  the  acids  is  much  more  marked  when  they 
are  applied  to  the  less  resistant  Mucous  Membranes.  Even  small  quan- 
tities of  strong  sulphuric  acid  striking  the  eye  are  sufficient  to  destroy 
the  sight. 

In  the  Mouth,  (Esophagus,  and  Stomach  the  corrosive  action  is  evi- 
denced by  complete  destruction  of  the  mucous  membranes  which  come 
in  contact  with  the  strong  acid.  The  oesophagus  and  stomach  may  be 
perforated,  and  this,  along  with  the  shock  and  collapse,  often  proves 
immediately  fatal,  or  if  the  patient  recovers  temporarily,  the  erosions 
may  give  rise  to  cicatricial  contractions  and  death  from  inanition. 
Hydrochloric  acid  and  the  stronger  organic  acids  are  capable  of  caus- 
ing corrosion  of  the  mucous  membranes,  but  this  is  not  so  extensive 
generally  as  that  following  nitric  and  sulphuric  acid.  The  corrosion 
from  acids  differs  from  that  from  alkalies,  in  the  tissues  being  shrunken, 
hard  and  brittle,  while  after  a  caustic  alkali  they  are  soft  and  swollen 
and  have  a  slimy  soapy  appearance. 

The  symptoms  of  corrosive  acid  poisoning  are  intense  pain  in  the 
mouth,  throat  and  stomach,  vomiting  and  often  diarrhoea,  shock  and 
collapse,  with  rapid,  weak  pulse  and  shallow  respiration.  The  tem- 
perature is  often  subnormal,  and  death  occurs  in  the  course  of  a  few 
hours.  When  fuming  acids  are  swallowed,  and  especially  in  poisoning 
with  hydrochloric  acid,  the  irritant  vapor  passing  into  the  respiratory 
passages  may  cause  spasm  of  the  glottis,  or  oedema  of  the  larynx,  and 
prove  immediately  fatal  from  asphyxia.  Even  one  part  of  hydro- 
chloric acid  vapor  in  20,000  of  air  causes  sneezing  and  pain  in  the 
throat  and  chest  (Lehmann). 

Dilute  solutions  of  the  acids  have  a  characteristic  taste,  and  induce  a 
reflex  flow  of  saliva  and  an  astringent  feeling  in  the  mouth  and  throat 
from  their  causing  a  coagulation  of  the  superficial  layers  of  proteids. 
In  the  stomach  they  displace  any  weaker  acids  from  their  combinations 
with  bases,  and  may  have  some  antiseptic  action.  The  gastric  juice  is 
normally  acid,  containing  about  0.2  per  cent,  of  free  hydrochloric  acid, 
and  this  acid  reaction  is  essential  to  the  action  of  pepsin.  Other  acids 
may  replace  the  hydrochloric  acid  in  digestion,  and  a  good  deal  of 
work  has  been  done  in  determining  the  relative  value  of  the  acids  for 
this  purpose.  This  is  done  by  adding  different  acids  to  solutions  of 
pepsin  in  test-tubes,  and  noting  the  amount  of  fibrin  or  other  proteid 
which  is  digested  in  the  course  of  a  number  of  hours.  These  experi- 
ments have  shown  that  hydrochloric  is  better  than  most  other  acids, 
but  is  perhaps  surpassed  by  hydrofluoric  and  oxalic  acids  ;  but  the  re- 
sults seem  to  vary  with  the  particular  pepsin  used,  that  obtained  from 
the  dog  and  calf  differing  somewhat  in  its  relations  to  acids  from  that 
of  the  child.  Their  poisonous  action  precludes  the  use  of  either  flu- 
oric or  oxalic  acid  in  the  stomach,  and  the  other  acids  seem  inferior  to 


ACIDS.  557 

hydrochloric  acid,   so   that   both   clinical   experience  and   experiment 
point  to  the  last  as  the  most  suitable  acid  for  use  in  the  stomach. 

The  acids  are  absorbed  from  the  alimentary  canal  fairly  rapidly  in 
most  cases.  In  the  Blood  and  Tissues  they  do  not  exist  as  acids  but 
as  salts,  for  the  reaction  of  the  blood  must  remain  slightly  alkaline 
throughout  life,  and  if  sufficient  acid  be  given  to  neutralize  the  alka- 
lies of  the  body,  the  animal  dies  before  the  blood  becomes  neutral,  al- 
though after  death  it  may  be  found  to  be  acid.  The  means  provided 
by  the  economy  to  neutralize  acids  differ  in  different  animals ;  in  the 
herbivora  the  fixed  alkalies  of  the  blood  and  tissues  are  called  upon 
chiefly,  and  if  more  acid  be  absorbed  than  can  be  neutralized  by  these, 
the  animal  dies  ;  in  the  carnivorous  animals  and  in  man,  a  further  pro- 
tective mechanism  exists,  for  in  these  ammonia  is  liberated  by  the  tis- 
sues, and  serves  to  neutralize  the  acid,  and  thus  saves  the  fixed  alka- 
lies. The  difference  is  relative  and  not  absolute,  however,  for  the 
herbivora  also  develop  some  ammonia,  and  the  carnivora  employ  some 
of  the  fixed  alkalies  to  preserve  the  normal  reaction  of  the  tissues. 
Man  appears  to  stand  midway  between  the  two  classes,  for  while  am- 
monia appears  in  the  urine  after  acid  absorption,  the  fixed  alkalies  are 
also  present  in  excess.  Much  larger  amounts  of  dilute  acids  may 
therefore  be  absorbed  without  serious  symptoms  by  man  and  by  the 
carnivora  than  by  the  herbivora.  The  explanation  of  this  difference 
between  the  flesh-eating  and  the  plant-eating  animals  is  to  be  found  in 
the  nature  of  their  food.  The  flesh-eaters  are  accustomed  to  the  for- 
mation of  some  acid  in  their  tissues,  because  the  alkalies  of  their  food 
are  insufficient  to  neutralize  the  acids  formed  by  the  oxidation  of  the 
organic  matter,  and  they  would  gradually  be  deprived  of  all  their  al- 
kaline salts,  therefore,  were  they  not  protected  by  the  formation  of 
ammonia.  On  the  other  hand,  the  herbivorous  animals  absorb  much 
larger  quantities  of  the  organic  salts  of  the  alkalies  in  their  food,  and 
these  forming  carbonates  in  the  body,  serve  to  neutralize  what  acid  is 
formed  in  the  tissues.  In  ordinary  circumstances,  therefore,  they  have 
no  need  to  protect  the  fixed  alkalies,  and  are  unprovided  with  any 
mechanism  for  this  purpose.  When  an  excess  of  acid  is  absorbed, 
they  neutralize  it  by  means  of  the  fixed  alkali  of  the  tissues  and  blood, 
and  this  leads  to  a  lessened  alkalinity  of  the  blood,  which  becomes 
unable  to  carry  so  much  carbonic  acid  from  the  tissues  to  the  lungs. 
Thus  in  acid  poisoning  in  rabbits,  the  alkalinity  of  the  blood  has  been 
found  to  be  so  greatly  reduced  that  instead  of  containing  some  25  vol- 
umes of  carbonic  acid  per  cent,  of  blood,  it  carried  only  two  volumes 
per  cent,  or  very  little  more  than  could  be  dissolved  in  the  same 
amount  of  water.  When  this  occurs,  the  tissues  are  unable  to  rid 
themselves  of  their  carbonic  acid,1  and  a  series  of  symptoms  follow, 
commencing  in  deep,  labored,  rapid,  afterwards  shallow  respiration  ; 
the  heart  is  weak,  a  condition  of  collapse  follows,  and  eventually  the 

1  This  is  the  explanation  universally  adopted,  but  Loewy  and  Munzer  have  recently 
shown  that  some  additional  factor  is  involved  in  the  action  of  acids  on  herbivora. 
Spiro  states  that  in  some  cases  the  acid  is  excreted  in  the  urine  with  greater  difficulty 
in  the  herbivora  than  in  the  carnivora. 


558  INORGANIC  SALTS,  ACIDS  AND  BASES. 

respiration  ceases,  the  heart  continuing  to  beat  for  some  time  longer. 
The  quantity  required  to  poison  a  rabbit  in  this  way  is  about  1  G.  of 
hydrochloric  acid  for  each  kilogm.  body  weight.  The  injection  of 
sodium  carbonate,  even  in  the  last  stage  of  intoxication,  is  followed  by 
rapid  recovery,  from  more  alkali  being  supplied  the  blood  and  tissues, 
while  other  carbonates  are  not  so  useful  owing  to  the  action  of  the 
basic  ion.  The  blood-pressure  in  rabbits  is  much  reduced  by  the  acids, 
from  depression  of  the  vaso-motor  centre  and  the  heart.  In  carnivora 
and  man,  the  absorption  of  dilute  acids  does  not  alter  the  alkalinity  of 
the  blood  to  any  marked  degree,  and  no  serious  symptoms  arise  from 
this  cause. 

The  salts  formed  in  the  blood  and  tissues  after  the  absorption  of 
acids  are  rapidly  Excreted  by  the  kidneys,  which  however  retain  as 
much  alkali  as  possible  in  the  body  and  thus  excrete  the  salts  in  an 
acid  form.  Hence  there  arises  in  some  cases  irritation  of  the  kidneys, 
with  albumin,  and  even  blood,  in  the  urine,  which  is  rendered  more  acid 
than  usual  and  causes  a  sensation  of  heat  and  smarting  in  the  bladder 
and  urethra.  In  the  herbivora  the  reaction  changes  from  alkaline  to 
strongly  acid,  and  large  quantities  of  the  salts  of  the  alkalies  appear, 
while  in  the  carnivora  some  increase  in  the  sodium  and  potassium  of 
the  urine  occurs  along  with  a  much  greater  increase  in  the  ammonia. 
The  total  nitrogen  is  somewhat  increased  from  the  large  amount  of 
ammonia,  but  the  urea  is  slightly  decreased.  Some  authors  have  found 
an  augmented  excretion  of  lime  in  the  urine,  while  others  state  that  it 
is  less  than  usual. 

Not  infrequently  fatty  degeneration  of  the  heart,  liver,  muscles  or  kidney 
has  been  observed  in  corrosive  acid  poisoning,  when  the  patient  survived 
for  a  few  days,  and  Fraenkel  and  Reiche  found  a  form  of  necrosis  of  the  renal 
cells  in  these  cases.  These  changes  are  not  due  to  free  acid  in  the  blood, 
but  their  exact  cause  has  not  been  satisfactorily  determined. 

The  prolonged  treatment  of  animals  with  acids  has  been  found  to  be  fol- 
lowed by  anaemia  and  loss  of  flesh  and  strength,  which  are  probably  attri- 
butable to  the  disturbance  of  the  digestion  and  not  to  any  specific  action  of 
the  acids. 

Acids  applied  directly  to  the  living  tissues  lessen  their  vitality,  and  un- 
less there  is  sufficient  alkali  present  to  neutralize  them,  soon  destroy  it 
entirely.  In  some  cases  they  tend  to  cause  a  temporary  increase  in  activity 
at  first ;  thus  the  cilia  of  ciliated  epithelium  have  been  found  to  move  more 
rapidly  at  first  in  very  dilute  acids  and  then  to  cease  all  movement,  while 
muscle  seems  to  be  rendered  weaker  and  less  irritable  at  once.  As  in  the  case 
of  alkalies,  Loeb  finds  that  dilute  acid  causes  muscle  to  imbibe  more  water 
than  salt  solution  does,  and  Hamburger  finds  that  the  red  blood  cells  are 
increased  in  size  by  the  addition  of  small  quantities  of  acid  to  the  blood  out- 
side the  body.  The  frog's  heart  is  weakened  and  dilated  by  the  addition  of 
acid  to  a  perfusing  solution,  and  the  muscular  wall  of  the  vessels  also  re- 
laxes. The  addition  of  acids  to  the  blood  tends  to  agglutinate  the  red  cells  and 
to  form  methsemoglobin. 

Therapeutic  Uses. — The  acids  are  used  in  medicine  only  to  a  limited 
extent,  and  some  of  the  official  preparations  might  well  be  dispensed 
with. 


ACIDS.  559 

They  may  be  employed  to  give  flavor  to  draughts  in  fever  and  in  the  thirst 
of  diabetes,  the  most  popular  forms  being  those  formed  from  fruits,  such  as 
lemons,  limes,  or  grapes.  The  taste  is  due  to  the  sugars,  acids,  and  volatile 
oils  of  the  fruits,  and  is  modified  by  the  presence  of  inert  colloid  substances, 
such  as  the  pectins.  The  acids,  of  which  citric,  tartaric  and  malic  are  the 
chief,  are  very  important  factors  in  the  effect,  for  if  these  be  neutralized,  the 
fruit  juices  become  insipid,  and  do  not  quench  thirst  so  thoroughly.  The  so- 
called  grape  cure,  in  which  very  large  qualities  of  grapes  are  eaten,  owes 
most  of  its  value  to  the  large  amount  of  water  taken,  although  the  acids  and 
salts  may  act  as  aperients  in  the  same  way  as  the  saline  cathartics.  Instead 
of  the  fruit  juices,  carbonic  acid  waters  may  be  advised,  and  occasionally 
other  acids,  such  as  phosphoric  or  sulphuric,  are  prescribed  to  give  flavor. 

Acids  are  also  used  in  certain  forms  of  dyspepsia  in  which  the  hy- 
drochloric acid  of  the  stomach  is  deficient.  Hydrochloric  acid  is  most 
frequently  prescribed  for  this  purpose,  although  nitric  and  nitrohydro- 
chloric  acids  have  also  some  reputation ;  the  hydrochloric  acid  is 
certainly  more  efficient  than  these  in  test-tube  experiments  on  di- 
gestion. The  forms  of  dyspepsia  thus  treated  are  generally  those  aris- 
ing from  a  sedentary  life  or  in  the  course  of  convalescence,  and  the 
acids  are  often  prescribed  along  with  the  bitter  stomachics  and  are  to 
be  taken  about  half  an  hour  before  meals.  Irritation  of  the  stomach, 
or  hyperacidity  of  the  gastric  juice  is  of  course  a  contraindication. 

In  cases  of  alkaline  poisoning,  the  acids  are  the  natural  treatment ; 
the  organic  acids  should  be  preferred  for  this  purpose,  as  they  are  less 
liable  to  cause  additional  corrosion,  and  acetic  acid  in  the  form  of  vine- 
gar is  more  likely  to  be  at  hand  than  any  other. 

In  every  case  in  which  acids  are  prescribed  internally,  they  have  to 
be  given   largely  diluted,  as  otherwise  they  irritate  the  throat  and 
stomach.      They  are  taken  through  a  glass  tube,  in  order  to  prevent ^ 
as  far  as  possible  their  action  on  the  teeth. 

Strong  acids  have  some  effect  in  arresting  hemorrhage  (styptics) 
when  applied  directly  to  the  bleeding  point,  but  are  much  inferior  to 
some  of  the  metallic  salts,  such  as  the  iron  perchloride. 

Externally,  the  acids  are  used  to  some  extent  as  corrosives,  strong 
nitric  acid  being  not  infrequently  used  to  destroy  small  tumors,  to 
cauterize  the  os  uteri  and  for  similar  objects.  Its  action  is  more  easily 
localized  than  that  of  potash  and  on  the  other  hand  is  more  powerful 
than  the  metallic  salts  such  as  silver  nitrate  and  zinc  chloride.  In 
dilute  solution,  they  are  sometimes  applied  to  the  skin  to  lessen  ex- 
cessive local  sweating  and  diluted  vinegar  is  often  used  to  sponge  fever 
patients. 

In  cases  of  corrosive  Poisoning  with  acids,  the  first  indication  is  to 
neutralize  the  acids  as  far  as  possible  by  giving  alkalies.  These  ought 
not  to  be  in  themselves  corrosive,  arid  the  best  antidote  is  therefore 
the  insoluble  magnesia  and  magnesium  carbonate.  Lacking  these, 
the  most  readily  accessible  alkali  is  the  best,  and  the  lime  may  be 
scraped  from  walls  or  ceiling,  or  chalk,  soap,  or  wood  ashes  may  be 
given.  The  walls  of  the  stomach  and  oesophagus  may  also  be  pro- 
tected by  giving  milk  or  white  of  egg,  or  the  acid  may  be  rendered 
less  corrosive  by  diluting  it  with  large  quantities  of  water. 


560  INORGANIC  SALTS,   ACIDS  AND  BASES. 

BIBLIOGRAPHY. 

Walter.     Arch,  f.  exp.  Path.  u.  Pharm.,  vii.,  p.  148. 
Salkowski.     Virchow's  Arch.,  Iviii.,  p.  1. 
Jacquet.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxx.,  p.  311. 
Hahn.     Virchow's  Arch.,  cxxxvii.,  p.  597. 
Jaworski.     Deutsch  med.  Woch.,  1887,  Nos.  36-38. 
Hiibner.     Fortschritte  der  Med.,  xii.,  p.  163. 
Fraenkelu.  Reiche.     Virchow's  Arch.,  cxxxi.,  p.  130. 
Wroblewski.     Zeitschr.  f.  phys.  Chem.,  xxi.,  p.  1. 
Runge.     Arch.  f.  exp.  Path.  u.  Pharm.,  x.,  p.  324. 
Freudberg.     Virchow's  Arch.,  cxxv.,  p.  566. 
Dunlop.     Journ.  of  Phys.,  xx.,  p.  82. 
Loeb.     Pfltiger's  Arch.,  Ixix.,  p.  1  ;  Ixxiii.,  p.  422. 
Winterberg.     Ztschr.  f.  phys.  Chem.,  xxv.,  p.  202. 
Limbeck.     Ztschr.  f.  klin.  Med.,  xxxiv.,  p.  419. 
Loewyu.  Munzer.     Arch.  f.  [Anat.  u.]  Phys.,  1901,  p.  81. 
Spiro.     Beitrage  z.  phys.  und  path.  Chemie,  i.,  p.  269. 
Compare  Alkaline  Hydrates  and  Carbonates,  page  547. 

For  the  specific  effects  of  the  anions  of  the  acids,  see  chlorides,  phosphates,  acetate^, 
oxalates,  etc. 

Sulphuric  Acid. 

Sulphuric  acid  is  one  of  the  most  corrosive  acids  when  it  is  applied  in 
concentrated  form,  and  often  induces  complete  charring  of  the  tissues,  and  a 
coal-black  slough. 

Acidum  Sulphuricum  (U.  S.  P.,  B.  P.),  concentrated  sulphuric  acid,  con- 
taining at  least  92.5  per  cent,  by  weight  of  absolute  sulphuric  acid  U.  S.  P., 
containing  98  per  cent.  B.  P. 

Acidum  Sulphuricum  Dilutum  (U.  S.  P.,  B.  P.)  contains  10  per  cent.  U.  S.  P., 
13.65  per  cent.  B.  P.  of  absolute  sulphuric  acid.  0.6-2  c.c.  (10-30  mins.). 

Acidum  Sulphuricum  Aromaticum  (U.  S.  P.,  B.  P.)  is  an  alcoholic  solution 
flavored  with  ginger  and  cinnamon.  The  IT.  S.  P.  preparation  contains  20 
per  cent.,  the  B.  P.  preparation  13.8  per  cent,  of  sulphuric  acid.  0.3-1  c.c. 
(5-15  mins.)  in  a  glass  of  water. 

Sulphuric  acid  and  its  preparations  are  not  largely  used.  It  is  occasionally 
applied  as  a  caustic,  but  nitric  acid  is  generally  preferred.  Internally  it  is 
largely  used  as  a  prophylactic  and  remedy  in  lead  poisoning,  but  it  is  prob- 
ably of  little  value  here.  (See  Lead.)  It  has  also  been  advised  in  a  number 
of  conditions,  such  as  diarrhoea,  cholera,  night  sweats,  but  has  not  proved 
efficacious  in  any  of  them.  When  prescribed  internally  the  aromatic  acid  is 
the  best  form,  but  sulphuric  acid  could  be  dispensed  with  entirely  in  thera- 
peutics. 

Nitric  Acid. 

Nitric  acid  is  equal  or  superior  to  sulphuric  in  its  corrosive  action.  It  stains 
the  skin  and  tissues  a  bright  yellow  or  yellowish-brown,  and  this  serves  to  dis- 
tinguish cases  of  poisoning  under  the  two  acids. 

Acidum  Nitricum  (U.  S.  P.,  B.  P.)  contains  68  per  cent,  of  absolute  nitric 
acid  (HNO3)  (B.  P.  70  per  cent.). 

Acidum  Nitricum  Dilutum  (U.  S.  P.,  B.  P.)  contains  10  per  cent.  U.  S.  P., 
17.44  per  cent.  B.  P.  by  weight  of  absolute  nitric  acid.  0.6-2  c.c.  (10-30 
mins.). 

A  glass  rod  dipped  in  concentrated  nitric  acid  is  used  as  a  corrosive.  The 
dilute  acid  has  been  advised  in  dyspepsia,  but  is  generally  considered  in- 
ferior to  hydrochloric  acid,  and  has  been  shown  to  be  much  less  efficient  in 
artificial  digestion.  It  has  also  some  reputation  in  certain  liver  diseases, 
but  is  supposed  to  be  inferior  to  the  nitrohydrochloric  acid.  Nitric  acid  is 
occasionally  used  in  some  intestinal  conditions  accompanied  by  diarrhoea. 


ACIDS.  561 

Hydrochloric  Acid. 

Hydrochloric  acid  is  less  corrosive  than  the  two  preceding  acids,  and 
tends  to  cause  blistering  on  the  skin  rather  than  necrosis.  It  may  cause 
actual  loss  of  substance,  however,  when  applied  to  the  mucous  membranes 
in  concentrated  form,  and  stains  the  mouth  a  whitish  color. 

Acidum  Hydrochloricum  (U.  S.  P.,  B.  P.),  muriatic  or  hydrochloric  acid, 
contains  31.9  per  cent,  by  weight  of  the  gas  HC1.  (B.  P.  31.79  per  cent.) 

Acidum  Hydrochloricum  Dilutum  (U.  S.  P.,  B.  P.)  contains  10  per  cent. 
(B.  P.  10.58  per  cent.)  of  hydrochloric  acid  gas.  0.3-2  c.c.  (5-30  mins.)  in 
a  glass  of  water. 

Concentrated  hydrochloric  acid  is  scarcely  used  in  therapeutics.  The 
diluted  acid  is  often  prescribed  in  dyspepsia  in  which  there  seems  to  be  a 
deficiency  of  the  natural  acid  secretion.  In  cases  of  diarrhoea  in  which 
excessive  putrefaction  of  the  intestinal  contents  is  present,  it  may  be  of 
benefit  when  prescribed  along  with  other  drugs  ;  this  action  is  probably 
explained  by  its  disinfecting  the  stomach  contents,  as  the  hydrochloric  acid 
of  the  gastric  secretion  normally  does  ;  for  the  double  sulphates  of  the  urine 
certainly  diminish  under  its  use  in  many  cases.  It  is  said  that  hydrochloric 
acid  prevents  the  lactic  fermentation  in  1  :  1,000  dilution,  and  that  in  addi- 
tion to  its  action  on  the  digestive  ferment  it  increases  the  peristalsis  of  the 
stomach. 

BIBLIOGRAPHY. 

Cohn.     Zts.  f.  phys.  Chem.,  xiv.,  p.  74. 
Hirschfeld.     Pfliiger's  Arch.,  xlvii.,  p.  510. 
Kast.     Maly's  Jahresbericht,  1889,  xix.,  p.  271. 
Schuele.     Ztschr.  f.  klin.  Med.,  xxix.,  p.  67. 
Lehmann.     Arch.  f.  Hygiene,  v.,  p.  1. 

Nitrohydrochloric  Acid. 

Nitrohydrochloric  acid  is  formed  by  mixing  hydrochloric  and  nitric  acid, 
and  contains  not  only  the  original  acids,  but  a  number  of  decomposition 
products,  such  as  chlorine,  nitroxychloride  (NOC1)  and  nitrous  acid.  The 
strong  acid  (aqua  regia)  is  the  most  powerful  solvent  and  oxidizing  agent 
known,  dissolving  such  refractory  metals  as  platinum  and  gold. 

Acidum  Nitrohydrochloricum  (U.  S.  P.),  nitromuriatic  acid,  aqua  regia,  is 
formed  by  mixing  180  parts  of  nitric  acid  with  820  parts  of  hydrochloric  acid. 

Acidum  Nitrohydrochloricum  Dilutum  (U.  S.  P.)  is  formed  by  mixing  40  c.c. 
of  nitric  acid  with  180  of  hydrochloric  and  diluting  the  whole  to  one  litre. 
0.5-1  c.c.  (5-15  mins.). 

Acidum  Nitrohydrochloricum  Dilutum  (B.  P.)  is  formed  by  mixing  6  parts 
of  nitric  acid  and  8  parts  of  hydrochloric  acid  with  50  of  distilled  water. 
5-20  mins. 

The  diluted  acid  alone  is  used  in  therapeutics,  and  does  not  seem  so  efficient 
in  ordinary  dyspepsia  as  the  dilute  hydrochloric  acid,  but  has  some  reputation 
in  the  treatment  of  liver  diseases  and  jaundice,  though  no  explanation  of  its 
action  in  these  conditions  has  been  offered.  The  acids  cannot  act  as  such 
except  in  the  alimentary  canal,  but  in  the  nitrohydrochloric  acid  other  con- 
stituents, such  as  chlorine,  are  present,  and  it  is  conceivable  that  some  of 
these  may  have  a  specific  effect  on  the  liver  ;  further  proof  would  seem  to 
be  required,  however,  that  the  treatment  is  really  of  value.  The  acid  is 
ordinarily  given  by  the  mouth,  but  some  authorities  advise  that  it  be  applied 
in  the  form  of  a  foot-bath  or  of  an  ordinary  bath,  and  others  apply  it  in  a 
compress  over  the  liver.  These  external  applications  are  stated  to  be  even 
more  efficacious  in  hepatitis  than  the  internal  administration,  and  this  serves 
only  to  strengthen  the  doubt  of  the  value  of  the  remedy,  for  it  is  contrary 
to  all  experience  that  such  bodies  should  be  absorbed  in  any  quantity  from 
the  skin,  and  their  local  action  as  cutaneous  irritants  does  not  differ  from 
that  of  other  drugs. 
36 


562  INORGANIC  SALTS,   ACIDS  AND  BASES. 

Phosphoric  Acid. 

Phosphoric  acid  is  much  less  corrosive  and  irritant  than  the  other  miners 
acids,  but  in  large,  concentrated  doses  may  cause  gastro-enteritis. 

Acidum  Phosphoricum  (U.  S.  P.)  contains  85  per  cent.,  Acidum  Phosphor 
cum  Concentratum  (B.  P.),  66.3  per  cent,  of  absolute  phosphoric  acid  (H3PO4 

Acidum  Phosphoricum  Dilulum  (U.  S.  P.,  B.  P.)  contains  10  per  cent.,' U.  £ 
P.,  and  13.8  per  cent.,  B.  P.,  of  phosphoric  acid.  0.3-1.3  c.c.  (5-20  mins. 

Phosphoric  acid  has  been  used  to  some  extent  to  form  cooling  draughts  i 
fever.  It  has  also  been  prescribed  in  various  cachectic  conditions  on  tt 
theory  that  these  were  due  to  a  deficiency  of  phosphates  in  the  food  an 
tissues  ;  but  it  has  never  been  shown  to  be  of  any  benefit,  and  experimem 
have  proved  that  the  animal  tissues  are  unable  to  build  up  phosphori 
compounds  from  the  inorganic  phosphates. 

Sulphurous  Acid. 

Sulphurous  acid  differs  from  the  preceding  members  of  the  group  i 
its  powerful  reducing  action,  through  which  it  becomes  oxidized  to  sul 
phuric  acid,  and  which  renders  it  strongly  poisonous  to  protoplasm  i 
general,  quite  apart  from  its  acidity.  Sulphurous  acid  anhydride  : 
accordingly  used  to  a  considerable  extent  to  disinfect  rooms  and  furn 
ture  after  infectious  diseases  ;  for  this  purpose  sulphur  is  burned  in  It 
room,  which  ought  to  be  rendered  as  air-tight  as  possible,  and  tli 
fumes  are  allowed  to  act  for  several  hours  before  the  room  is  ventilatec 
The  value  of  this  method  of  disinfection  has  been  called  in  questioi 
but  there  is  no  doubt  that  sulphurous  acid  gas  is  fairly  germicidal  whe 
it  is  applied  along  with  moisture.  It*  is  not  capable  of  such  a  wide  aj 
plication  as  formaline,  because  sulphurous  acid  bleaches  many  colorin 
matters,  and  the  procedure  is  open  to  the  objection  that  it  may  lend 
sense  of  security  which  is  quite  unwarranted,  and  may  lead  to  the  neg 
lect  of  other  measures.  The  disinfection  to  be  of  any  value  must  b 
thoroughly  carried  out,  and  can  only  be  applied  to  inanimate  objects,  a 
the  fumes  are  fatal  to  the  higher  animals,  even  when  much  less  conceu 
trated  than  are  necessary  to  destroy  bacteria.  In  order  to  be  of  service 
at  least  one  volume  of  SO2  ought  to  be  present  in  each  hundred  volume 
of  air,  and  even  this  concentration  is  insufficient  to  destroy  the  spores  c 
bacteria.  Novy  *  recommends  3-6  pounds  of  sulphur  to  be  burned  fo 
each  1,000  cubic  feet  of  space;  the  walls  and  floor  should  be  sprayed  wit] 
water,  and  the  room  must  be  kept  perfectly  closed  for  at  least  20  hours 

The  chief  symptoms  of  poisoning  with  sulphurous  acid  are  those  o 
irritation  of  the  mucous  membranes,  and  if  the  solution  be  swallowe< 
these  may  not  differ  from  those  of  the  other  acids.  Sulphurous  aci< 
penetrates  the  tissues  more  rapidly  than  most  of  the  others  owing  t< 
its  gaseous  form,  and  does  not  cause  actual  loss  of  substance  as  sul 
phuric  acid  does. 

In  poisoning  from  the  inhalation  of  the  anhydride  on  the  other  hand 
the  symptoms  arise  chiefly  from  the  respiratory  tract.  Even  in  five  part 
in  10,000  it  acts  as  an  irritant,  causing  sneezing,  coughing  and  lachry 
mation,  and  in  somewhat  greater  concentration  it  becomes  entirely  ir 
respirable ;  still  smaller  quantities  in  the  air  cause  bronchial  irritatioi 

1  Novy  and  Waite.     Medical  News,  Ixxii.,  p.  641. 


ACIDS.  563 

and  catarrh,  when  inhaled  for  some  time.  Sulphurous  acid  is  neu- 
tralized and  oxidized  for  the  most  part  to  sulphates  in  the  tissues,  or 
probably  partly  in  the  course  of  absorption. 

The  solution  of  sulphurous  acid  of  the  pharmacopoeia  is  used  to  a 
limited  extent  as  an  antiseptic  solution  in  skin  diseases.  It  is  more 
irritant  to  the  broken  skin  than  many  other  equally  powerful  antiseptics. 

Acidum  Sulphurosum,  U.  S.  P. — A  solution  of  not  less  than  6.4  per  cent. 
by  weight  of  sulphurous  acid  gas  (SO2)  in  water.  B.  P.,  a  solution  contain- 
ing 6.4  per  cent,  of  hydrogen  sulphite  (H2SO3)  corresponding  to  5  per 
cent,  by  weight  of  sulphurous  anhydride  (SO2). 

Hydrofluoric  Acid  is  strongly  corrosive  and  prevents  the  growth  of  bac- 
teria in  solutions  of  one  per  mille.  After  absorption  it  induces  the  specific 
fluoride  action  (see  page  525). 

Organic  Acids  of  the  Fatty  Series. 

The  organic  acids  have  a  much  less  marked  local  action  than  the  inor- 
ganic, causing  little  or  no  corrosion  unless  when  applied  to  mucous  surfaces 
in  very  concentrated  form.  They  are  absorbed  as  salts  of  the  alkalies,  but 
do  not  as  a  general  rule  reduce  the  alkalinity  of  the  blood  or  render  the 
urine  more  acid,  because  they  are  oxidized  to  carbonates  in  the  tissues.  Ox- 
alic acid  is  the  chief  exception  to  this  rule,  but  the  specific  action  of  the  ox- 
alates  is  powerful  enough  to  conceal  the  acid  action  to  a  great  extent. 

Acetic  Acid  applied  in  concentrated  solution  to  the  skin  causes  irritation 
and  congestion  and  eventually  blistering,  but  does  not  induce  necrosis  ex- 
cept of  the  most  superficial  layers.  The  congestion  is  often  followed  by 
marked  pallor  instead  of  by  blistering  ;  and  this  has  been  explained  by  con- 
traction of  the  vessels,  but  may  be  due  to  a  precipitation  of  the  proteids  of 
the  skin.  In  the  mouth  and  stomach  it  acts  as  an  irritant,  causing  vomiting, 
great  pain,  collapse  and  even  death  ;  the  epithelium  is  found  thickened 
and  occasionally  contains  haemorrhages.  Dilute  acetic  acid  (vinegar)  has 
little  effect  apart  from  its  acid  taste,  and  is  used  largely  as  a  flavoring  agent 
and  condiment.  The  prolonged  use  of  large  quantities  may  however  give 
rise  to  gastric  irritation  and  to  loss  of  appetite  and  weight. 

Acidum  Aceticum  Glaciale  (U.  S.  P.,  B.  P.)  (HC2H3O2)  is  almost  absolute 
acetic  acid  (99  per  cent.),  and  becomes  crystalline  at  a  temperature  some- 
what below  15°  C.  (60°  F.). 

Acidum  Aceticum  (U.  S.  P.,  B.  P.)  contains  36  per  cent,  of  absolute  acetic 
acid  U.  S.  P.,  33  per  cent.  B.  P. 

Acidum  Aceticum  Dilutum  contains  6  per  cent,  of  absolute  acetic  acid 
U.  S.  P.,  4.27  per  cent.  B.  P.  (Dilute  acetic  acid  is  used  to  form  the  official 
aceta  except  the  Acetum  Cantharidis,  B.  P.)  2-8  c.c.  (£-2  fl.  drs.). 

Acetic  acid  is  sometimes  applied  to  the  skin  as  a  slight  local  irritant  in 
contusions,  and  in  very  dilute  solutions  to  cool  the  surface  and  to  prevent 
excessive  local  perspiration.  It  has  been  used  as  a  styptic  in  slight  haemor- 
rhage, and  may  be  inhaled  for  this  purpose  in  epistaxis.  Vinegar  is  also 
inhaled  in  cases  of  fainting,  in  order  to  induce  a  reflex  stimulation  of  the 
vaso-motor  centre  through  irritation  of  the  nostrils.  In  cases  of  poisoning 
with  alkalies  vinegar  is  often  the  most  convenient  acid  and  in  addition  is 
less  likely  to  do  harm  than  the  inorganic  acids. 

Acetic  acid  itself  is  not  used  as  a  corrosive,  but  one  of  its  derivatives,  tri- 
chloracetic  acid  (CC13COOH),  has  been  employed  with  good  results. 

Formic  Acid  resembles  acetic  acid  in  most  points,  except  that  it  is  more 
volatile  and  more  irritant,  that  less  of  it  is  oxidized  in  the  tissues,  and  that 
given  in  large  quantities  it  is  said  to  induce  nephritis.  It  is  not  used  in 
therapeutics. 

The  other  acids  of  the  acetic  acid  series  resemble  acetic  acid  in  their  ef~ 


564  INORGANIC  SALTS,   ACIDS  AND  BASES. 

fects,  but  become  less  irritant  as  they  become  more  complex  and  less  easily  dig 
sociated. 

Lactic  Acid  resembles  acetic  acid  in  its  behavior  in  the  organism  (se 
page  550).  It  was  suggested  at  one  time  that  sleep  following  muscular  ex 
ertion  was  due  to  the  lactic  acid  formed  in  the  muscles,  and  this  acid  wa 
therefore  recommended  as  a  hypnotic,  but  has  been  shown  to  be  of  no  valu 
for  this  purpose.  Kickets,  rheumatism  and  other  diseases  were  also  at  on 
time  attributed  to  the  excessive  formation  of  lactic  acid  in  the  tissues,  bu 
this  theory  is  only  of  historical  interest.  Under  the  impression  that  lacti 
acid  was  the  normal  acid  of  the  gastric  digestion,  it  was  at  one  time  used  ii 
dyspepsia. 

Acidum  Lacticum  (U.  S.  P.,  B.  P.)  is  obtained  by  the  fermentation  of  mill 
sugar  or  grape  sugar,  and  contains  75  per  cent,  of  absolute  lactic  aci< 
(HCj^Og).  It  is  a  colorless  liquid  of  strong  acic1  taste. 

Lactic  acid  has  been  used  recently  as  a  caustic  application  to  malignan 
ulcers  and  diphtheritic  membranes. 

Oxalic  Acid  is  frequently  used  as  a  poison  by  suicides,  either  as  such  or  a 
the  acid  potassium  salt  (salt  of  sorrel  or  essential  salt  of  lemons).  Poisoning 
has  repeatedly  occurred  from  oxalic  acid  having  been  mistaken  for  magnesiun 
sulphate,  which  it  resembles  in  appearance.  The  symptoms  are  those  of  aci< 
poisoning,  along  with  the  specific  effects  of  the  oxalates  (see  page  553) 
Oxalic  acid  is  not  used  in  therapeutics,  although  it  has  been  said  to  be  bene 
ficial  in  amenorrhcea. 

Tartaric  Acid  induces  symptoms  of  gastric  irritation  when  taken  in  larg 
doses,  and  has  been  the  cause  of  fatal  poisoning  in  a  few  cases.  It  is  slowl; 
absorbed,  and  some  of  it  escapes  combustion  in  the  tissues  and  is  excreted  ii 
the  urine  in  the  form  of  the  acid  tartrate.  (See  Tartrates,  page  535.) 

Acidum  Tartaricum  (IT.  S.  P.,  B.  P.)  (H2C4H4O6),  colorless  crystals  ver 
soluble  in  water.  0.3-1.3  G.  (5-20  grs.). 

Tartaric  acid  is  prescribed  with  the  carbonates  and  bicarbonates  to  forn 
effervescent  draughts  ;  the  tartaric  acid  ought  to  be  slightly  in  excess  in  or 
der  to  lend  its  pleasant  acid  taste,  the  usual  proportion  being  about  eigh 
parts  of  acid  to  seven  parts  of  sodium  bicarbonate.  These  effervescent  mh 
tures  formed  with  the  tartrates  act  as  saline  cathartics  in  large  doses  (st 
page  537).  Tartaric  acid  may  be  prescribed  in  dilute  solution  with  sug£ 
and  a  drop  of  volatile  oil  as  a  lemonade,  which  is  cheaper  than  that  forme 
with  citric  acid. 

Citric  Acid  resembles  tartaric  acid  in  its  action,  but  appears  less  irritan 
and  no  case  of  serious  poisoning  is  recorded  from  its  use.  It  is  slowly  al 
sorbed  like  tartaric,  but  seems  to  be  almost  entirely  oxidized  in  the  tissue: 

Acidum  Citricum  (U.  S.  P.,  B.  P.)  (H3C6H.O7  •+•  H2O)  resembles  tartaric  aci 
in  its  properties  for  the  most  part.  0.3-1.3  G.  (5-20  grs.). 

Syrupus  Acidi  Citrici  (U.  S.  P.)  is  ordinary  syrup  to  which  one  per  cent.  ( 
citric  acid  and  spirit  of  lernon  have  been  added,  and  is  used  only  as  a  flavoi 

Citric  acid  is  used  to  form  lemonades  and  effervescent  draughts.  Fc 
lemonade  2-4  parts  of  citric  acid  may  be  dissolved  in  1,000  parts  of  watei 
some  sugar  and  a  few  drops  of  volatile  oil  being  added.  For  effervesce! 
solutions  about  8  parts  of  the  acid  may  be  prescribed  along  with  7  parts  < 
bicarbonate  of  soda,  with  directions  to  dissolve  the  two  powders  separately 
mix  the  solutions  and  drink  while  effervescing.  In  large  quantities  this  mh 
tare  acts  as  a  saline  cathartic ;  in  smaller  quantities  it  may  be  used  to  ii 
crease  the  alkalinity  of  the  blood,  and  to  render  the  urine  less  acid.  (Se 
pages  537  and  550.) 

Lime  juice  and  lemon  juice,  which  contain  considerable  amounts  of  fre 
citric  acid,  are  generally  preferred  to  the  pure  acid  for  lemonades  to  quenc 
the  thirst.  Lime  juice  has  been  found  of  great  benefit  as  a  prophylactic  i 
the  treatment  of  scurvy,  but  this  is  not  due  to  the  citric  acid,  but  to  som 
unknown  property  of  the  fruit  juices.  Citric  acid  has  been  used  in  rheumati 
affections,  without  any  marked  improvement  being  elicited,  according  to  tt 
best  observers. 


CALCIUM.  565 

XIX.     CALCIUM. 

The  salts  of  lime  are  present  in  very  large  amount  in  the  tissues  of 
animals,  and  considerable  interest  attaches  to  their  absorption,  excretion 
and  general  action.  They  form  the  great  mass  of  the  inorganic  con- 
stituents of  the  bones  and  teeth  of  the  vertebrates  and  of  the  shells  of 
the  invertebrates.  In  addition  it  has  been  shown  of  recent  years  that 
they  are  present  to  a  considerable  amount  in  the  soft  tissues  and  are, 
in  fact,  essential  to  many  forms  of  living  matter,  and  to  the  activity 
of  certain  ferments. 

Calcium  and  the  other  alkaline  earths  differ  from  the  alkalies  in 
possessing  comparatively  few  very  soluble  salts,  and  they  seldom  effect 
such  changes  in  the  physical  properties  of  the  fluids  of  the  body  as 
have  been  described  under  salt-action  and  chloride  of  sodium.  Even 
the  soluble  salts  penetrate  with  greater  difficulty  into  the  various  tissues 
of  the  body,  which  seem  to  have  much  less  affinity  for  them  than  for 
the  salts  of  the  alkalies.  They  precipitate  colloids,  such  as  the  proteids, 
in  much  more  dilute  solutions  than  the  alkalies,  and  the  precipitate  is 
not  redissolved  by  dilution  with  water. 

Action.  —  The  soluble  lime  salts  are  Absorbed  with  great  difficulty 
from  the  stomach  and  intestine,  and  retard  considerably  the  absorption 
of  fluid.  They  would  presumably  have  a  cathartic  action  were  they 
not  thrown  out  of  solution  very  readily  by  the  alkaline  fluids.  In 
addition  calcium  forms  insoluble  salts  with  all  of  the  cathartic  acid 
ions,  so  that  no  such  double  effect  can  be  obtained  as  is  seen  from  mag- 
nesium sulphate.  (See  Saline  Cathartics,  page  531.)  The  great  pro- 
portion of  the  lime  taken  either  in  the  food  or  as  a  remedy,  unquestion- 
ably leaves  the  body  in  the  stools  entirely  unabsorbed,  while  a  small 
quantity  of  it  is  taken  up  from  the  alimentary  canal  whether  the  lime  be 
administered  in  a  soluble  or  in  an  insoluble  form.  This  small  quan- 
tity circulates  in  the  blood,  probably  in  combination  with  proteids,  and 
is  slowly  excreted,  unless  there  is  a  deficiency  in  the  supply  of  lime, 
when  it  may  be  utilized  by  the  tissues.  When  larger  quantities  are 
thrown  into  the  blood  by  intravenous  or  hypodermic  injection,  the 
calcium  of  the  blood  remains  abnormally  high  for  some  time,  but  all 
the  calcium  thus  injected  is  not  in  the  circulation  throughout  its  stay 
in  the  body.  Some  of  it  is  temporarily  deposited  in  some  unknown 
organ,  and  is  gradually  withdrawn  and  excreted  after  the  first  excess 
is  eliminated. 

The  lime  is  Excreted  in  part  in  the  urine,  but  for  the  most  part 
through  the  epithelium  of  the  large  intestine.  Abel  and  Muirhead 
have  shown  that  some  of  the  calcium  ingested  in  the  form  of  the  hy- 
drate is  excreted  in  the  urine  as  calcium  carbamate  (Ca(CO2NH2)2)  and 
probably  other  salts  may  be  eliminated  in  part  at  any  rate  in  this 
form.  The  carbamate  is  a  very  unstable  salt,  and  breaks  up  in  the 
urine,  freeing  carbonic  acid  and  ammonia,  while  the  calcium  forms  the 
carbonate  of  lime ;  the  urine  is  often  alkaline  therefore,  and  smells 
strongly  of  ammonia.  Calcium  lessens  the  phosphates  of  the  urine, 


566  INORGANIC  SALTS,   ACIDS  AND  BASES. 

and  therefore  its  acidity,  by  forming  insoluble  phosphates  in  the 
bowel,  and  thus  preventing  the  absorption  of  the  phosphates  of  the 
food.  The  small  quantity  of  calcium  absorbed  from  the  alimentary 
canal  has  not  been  shown  to  have  any  action  except  in  replacing  the 
calcium  compounds  of  the  tissues.  Except  under  special  circum- 
stances, the  calcium  of  the  food  is  always  sufficient  to  supply  the  needs 
of  the  organism,  so  that  lime  salts  given  as  remedies  have  after  absorp- 
tion no  specific  action  due  to  the  calcium,  but  owe  their  activity  to  the 
anion  exclusively.  Thus,  calcium  bromide  may  have  some  effect  if 
absorbed,  but  this  effect  is  due  to  the  bromide  ion,  and  would  be  the 
same  if  an  equal  proportion  of  sodium  bromide  were  taken  up  by  the 
blood.  In  the  same  way  calcium  hydrate  when  absorbed  owes  its  ac- 
tivity to  its  alkalinity  (hydroxyl  ion)  and  not  to  the  calcium,  and 
apart  from  the  method  of  its  excretion,  has  the  same  effect  in  the  tissues 
as  an  equivalent  amount  of  sodium  hydrate. 

Soluble  calcium  salts  injected  directly  into  the  blood  vessels  seem  to  be 
poisonous,  though  further  study  of  their  action  is  required.  They  first 
accelerate  and  strengthen  the  heart,  and  in  large  quantities  bring  it  to  a  stand- 
still, and  also  have  a  marked  effect  in  contracting  the  vessels  when  perfused 
through  them.  They  depress  the  central  nervous  system,  causing  narcosis  and 
sleep,  during  which  some  authors  state  that  the  reflexes  remain  unaffected, 
while  others  found  them  much  depressed.  These  effects  are  absent  when 
the  salts  are  taken  up  from  the  bowel,  mainly  no  doubt  owing  to  their  slow 
absorption,  partly  perhaps  to  their  forming  albuminous  compounds  in  their 
passage  into  the  tissues. 

Lime  Starvation.  —  Excess  of  calcium  in  the  organism  is  therefore 
little  to  be  apprehended  from  the  ordinary  methods  of  administration, 
and  lime  salts  are  not  used  in  therapeutics  to  induce  changes  in  the 
organism  through  their  presence  in  excess  in  the  blood,  like  other 
remedies  such  as  morphine  or  strychnine.  Another  question  arises, 
however,  namely  whether  the  organism  may  not  be  rendered  abnormal 
by  a  deficiency  in  the  supply  of  lime,  and  whether  this  deficiency  may 
be  remedied  by  the  administration  of  calcium  salts. 

The  effects  of  a  deficiency  of  lime  in  the  food  have  been  the  subject 
of  several  very  careful  investigations,  and  while  the  adult  animal  does 
not  seem  to  suffer  greatly  from  a  very  considerable  reduction  of  the 
calcium  of  the  food,  young  growing  animals  have  at  the  hands  of  some 
investigators  developed  marked  abnormalities,  resembling  closely  those 
observed  in  rickets  and  osteomalacia  in  the  human  subject.  In  lime 
starvation,  as  in  rickets,  there  is  a  lessened  deposit  of  lime  in  the 
bones,  which  retain  their  cartilaginous  consistency  and  show  other 
deviations  from  the  normal  condition  ;  in  rickets  the  bones  alone  are 
involved,  while  in  animals  deprived  of  calcium  the  soft  tissues  also 
show  a  lessened  content  of  lime  salts.  Deficiency  of  the  lime  in  the 
food  naturally  affects  young  animals  more  than  adults,  because  the 
former  require  much  more  calcium  to  build  up  the  growing  skeleton. 

The  effects  of  the  withdrawal  of  lime  have  been  studied  in  some  Iso- 
lated Organs.  Thus  Ringer  compared  the  behavior  of  the  frog's  heart 
when  perfused  with  solutions  of  the  salts  of  the  alkalies  with  that  of 


CALCIUM.  567 

one  perfused  with  the  same  solutions  to  which  minute  traces  of  lime 
were  added,  and  found  that  the  efficiency  of  the  heart  was  much  in- 
creased and  that  it  survived  very  much  longer  under  the  latter  condi- 
tions ;  Locke  has  recently  shown  that  a  similar  relation  exists  between 
the  mammalian  heart  and  the  inorganic  elements  of  serum.  Lime  salts 
exercise  a  similar  effect  in  voluntary  muscle,  which  survives  much 
longer  when  perfused  with  salt  solution  containing  calcium  than  when 
sodium  chloride  solutions  alone  are  used.  Both  the  heart  and  skeletal 
muscle  eventually  cease  to  contract  on  electrical  stimulation  when  per- 
fused with  physiological  salt  solution,  but  recover  again  when  traces  of 
lime  salts  are  added  to  it.  In  the  same  way,  the  irritability  of  the 
frog's  nerve  persists  much  longer  in  salt  solution  containing  a  lime  salt 
than  in  unmixed  salt  solution,  and  may  be  restored  by  the  addition  of 
lime,  when  it  has  disappeared  after  the  prolonged  action  of  the  0.6 
per  cent,  chloride  of  sodium  solution.  Ciliated  epithelium  continues 
to  wave  rhythmically  much  longer  in  lime  solution  than  in  distilled 
water,  in  which  it  swells  up  and  rapidly  loses  its  activity.  This  prob- 
ably explains  the  observation  that  some  fish  die  very  soon  in  distilled 
water  but  survive  in  water  in  which  traces  of  lime  are  present.  Lime 
is  also  necessary  for  the  development  of  various  ova  ;  for  instance,  frog 
spawn  kept  in  water  devoid  of  lime  salts  fails  to  develop,  or  develops 
abnormally. 

Lime  salts  are  also  indispensable  in  some  processes  which  are  not 
dependent  on  the  presence  of  living  cells.  Thus  rennet  does  not  coagu- 
late milk  except  when  a  lime  salt  is  present,  and  the  Coagulation  of  the 
Blood  may  be  prevented  by  precipitating  its  calcium  salts  in  the  form 
of  oxalates.  Hammersten  has  recently  shown  that  the  lime  salts  are 
not  necessary  to  the  formation  of  fibrin,  for  this  occurs  in  oxalate 
solutions  if  fibrin-ferment  be  added  to  fibrinogen.  But  the  fibrin- 
ferment  is  not  formed  except  in  the  presence  of  calcium  salts,  and  when 
oxalates  are  added  to  the  blood  before  this  ferment  is  developed,  they 
prevent  its  formation  and  hinder  clotting.  When  lime  salts  are  added, 
the  ferment  is  liberated  and  coagulation  occurs  at  once.  In  other 
words,  lime  is  not  necessary  for  the  activity  of  the  fibrin-ferment,  but 
for  its  development  from  the  prothrombin  or  zymogen,  in  which  it  ex- 
ists in  the  circulating  blood. 

Other  ferments  act  in  the  absence  of  available  lime  salts.  Thus 
pepsin  digests  when  instead  of  hydrochloric,  oxalic  acid  is  added  to  it, 
but  it  is  unknown  whether  pepsin  is  formed  from  pepsinogen  in  the 
absence  of  lime. 

The  higher  organisms,  both  animals  and  plants,  have  thus  been 
shown  to  require  lime  for  some  of  their  functions,  and  it  is  probably 
necessary  for  many  others  in  which  its  importance  has  not  yet  been 
recognized.  The  lowest  forms  of  life,  however,  including  the  bacteria 
and  some  of  the  moulds,  seem  to  be  able  to  live  without  it.  In  order 
to  induce  the  effects  of  lime  starvation,  it  is  not  always  necessary  to 
withdraw  lime  from  the  food,  for  they  may  be  caused  by  the  presence 
of  any  substance  which  prevents  the  dissociation  of  the  calcium  ion. 


568  INORGANIC  SALTS,  ACIDS  AND  BASES. 

Thus,  oxalate  solutions  added  to  the  blood  or  milk,  or  to  the  nutrient  fluid 
for  perfusion  of  the  heart,  have  the  same  effects  as  the  withdrawal  of 
lime.  Food  containing  large  quantities  of  oxalate  salts  has  in  some 
cases  induced  symptoms  in  animals  resembling  those  of  lime  starvation, 
and  it  seems  possible  that  some  of  the  symptoms  of  fluoride  action  are 
also  explicable  from  their  precipitating  the  lime  salts  of  the  food  and 
of  the  blood. 

In  several  instances  a  curious  relationship  has  been  shown  to  exist  be- 
tween the  calcium  and  potassium  salts.  Thus  when  a  frog's  heart  is  per- 
fused with  sodium  chloride  solution  containing  a  trace  of  calcium,  the  move- 
ments are  not  entirely  normal,  the  contraction  being  somewhat  prolonged 
and  the  relaxation  much  retarded.  If  a  trace  of  potassium  chloride  is  added, 
however,  the  contraction  becomes  normal  in  character.  On  the  other  hand 
the  effect  of  potassium  on  the  frog's  heart  is  antagonized  by  the  addition  of 
lime.  The  same  holds  true  for  voluntary  muscle,  the  salts  of  calcium  tend- 
ing to  neutralize  the  effects  of  potassium,  and  vice  versa,  and  in  several  other 
relations  an  antagonism  has  been  observed  between  these  two  metals.  (See 
Ringer.) 

Another  question  that  has  excited  much  interest  recently  is  the  relation 
between  sodium  and  calcium.  It  has  already  been  noted  that  the  frog's 
heart  perfused  with  sodium  chloride  solution  soon  ceases  to  beat,  but  can  be 
restored  by  the  addition  of  calcium  and  potassium  to  the  circulating  medium. 
The  ordinary  explanation  (Kinger,  Howell)  is  that  the  calcium  and  potassium 
are  necessary  to  the  activity  of  the  heart  and  that  when  pure  salt  solution  is 
perfused,  these  elements  diffuse  into  it  and  are  lost  from  the  heart  muscle  ; 
this  diffusion  is  prevented  if  calcium  and  potassium  be  contained  in  the 
solution,  and  the  heart,  retaining  the  salts  essential  to  its  activity,  continues 
to  beat.  Another  explanation  has  been  offered  by  Loeb,  who  supposes  that 
the  lime  and  potassium  are  not  directly  essential,  but  that  they  neutralize 
the  poisonous  effects  of  sodium.  This  poisonous  action  of  sodium  has  not 
been  generally  recognized,  but  is  well  shown  by  the  behavior  of  a  small  fish 
(fundulus)  living  in  salt  water,  which  can  be  transferred  to  distilled  water 
without  injury,  thus  showing  that  neither  sodium  nor  calcium  is  necessary  in 
its  environment.  But  if  it  be  put  in  sodium  chloride  solution  of  the  same 
strength  as  sea  water  it  dies,  so  that  sodium  is  poisonous  to  it  unless  when 
antagonized  by  the  other  constituents  of  sea  water ;  the  essential  elements 
are  calcium  and  potassium,  for  when  these  are  added  to  the  injurious  sodium 
solution,  the  fish  lives  as  well  as  in  sea  water.  This  series  of  experi- 
ments certainly  forms  a  strong  support  for  Loeb's  theory  that  calcium  is  not 
directly  essential  to  rhythmic  movement,  but  only  neutralizes  the  effects 
of  sodium.  On  the  other  hand,  the  calcium  salts  themselves  are  poisonous  when 
they  are  not  counterbalanced  by  sodium  and  potassium  ;  in  this,  as  in  many  other 
instances,  there  must  be  maintained  between  the  inorganic  constituents  of  the 
surrounding  fluid  an  equilibrium,  such  as  exists  in  sea  water,  in  the  case  of  the 
fundulus  and  in  the  blood  plasma  in  the  case  of  the  heart  and  other  organs. 

The  salts  of  the  alkaline  earths  are  said  to  inhibit  the  hsemolytic  action  of  cer- 
tain serums,  while  those  of  the  alkalies  have  not  this  effect  when  applied  in  the 
same  concentration  ;  this  may  perhaps  be  connected  with  the  tendency  the  former 
have  to  coagulate  proteids.  The  formation  of  proteid  combinations  is  apparently 
the  explanation  of  the  disappearance  of  lime  salts  when  they  are  perfused  through 
organs  or  when  pieces  of  tissue  are  soaked  in  them. 

Therapeutic  Uses. — Calcium  salts  are  used  in  medicine  for  a  number 
of  different  purposes ;  thus  the  alkaline  preparations  may  be  prescribed 
to  lessen  the  acidity  of  the  stomach,  and  the  oxide  may  be  employed  as 
a  caustic.  But  these  owe  their  use,  not  to  the  calcium  ion,  but  to  the 


CALCIUM.  569 

other  part  of  the  molecule  —  the  anion.  As  a  matter  of  fact,  calcium  has 
no  important  effects  of  its  own  and  is  not  prescribed  for  any  action  which 
it  might  have  on  the  living  tissues.  The  question  has  been  raised,  how- 
ever, whether  calcium  may  not  be  given  therapeutically  to  supply  a 
deficiency  of  lime  in  the  body.  The  particular  conditions  which  have 
been  treated  on  this  theory  are  rickets  and  osteomalacia,  in  both  of 
which  there  is  unquestionably  too  little  lime  in  the  bones,  and  the  treat- 
ment has  been  thought  to  be  rational,  because  symptoms  similar  to 
those  of  rickets  have  been  induced  in  young  animals  whose  food  con- 
tained too  small  a  proportion  of  lime.  In  the  case  of  rickets  and  os- 
teomalacia, however,  there  is  no  reason  to  suppose  that  the  food  is 
deficient  in  calcium;  in  fact,  children  are  said  to  be  more  liable  to 
rickets  when  fed  on  cows7  milk  than  when  nursed  by  the  mother,  al- 
though the  milk  of  the  cow  contains  more  lime.  On  the  other  hand, 
patients  suffering  from  rickets  absorb  lime  and  excrete  it  again  in  ex- 
actly the  same  way  as  normal  persons,  and  although  their  bones  con- 
tain unusually  small  amounts  of  lime,  the  other  tissues  contain  rather 
more,  or,  at  any  rate,  not  less  than  normal.  Rickets  is  not  due  to  a 
lack  of  lime  in  the  food,  therefore,  nor  in  fact  in  the  tissues  generally, 
but  to  some  abnormal  condition  which  prevents  the  lime  salts  from 
being  deposited  in  the  bones,  although  they  are  present  in  abundance 
in  the  blood.  In  cases  of  lime  starvation  similar  symptoms  may  ap- 
pear, but  here  the  cause  is  the  want  of  lime,  which  is  not  presented  in 
sufficient  quantities,  although  the  bone-forming  cells  are  ready  to  de- 
posit it.  In  this  case  the  other  tissues  are  also  deficient  in  calcium  as 
well  as  the  bones.  From  these  considerations  it  follows  that  lime  salts 
are  not  likely  to  be  of  benefit  in  rickets  (£nd  the  same  holds  true  for 
osteomalacia),  unless  when  it  is  due  to  lime  starvation,  a  condition 
which  is  unlikely  to  arise  in  the  human  subject.  Experience  has 
demonstrated  also  that  the  lime  salts  are  quite  incapable  of  improving 
either  osteomalacia  or  rickets. 

It  has  also  been  proposed  to  treat  with  lime  cases  in  which  the  blood 
seemed  less  capable  of  clotting  than  normally —  particularly  haemophilia 
and  aneurism,  and  some  improvement  is  said  to  have  occurred  in  a  few 
instances.  Here  again,  however,  it  would  seem  to  be  very  improbable 
that  the  absence  of  coagulation  is  due  to  deficiency  in  the  lime  salts, 
for  much  more  is  taken  in  the  food  than  is  sufficient  for  the  organism, 
and  the  pharmacopoeial  salts  are  not  more  easily  absorbed  than  the 
combinations  present  in  food.  More  recently  the  treatment  has  been 
extended  to  forms  of  haemorrhage  in  which  there  is  no  reason  to  sup- 
pose that  the  coagulability  of  the  blood  is  reduced — haemoptysis,  gas- 
tric and  intestinal  haemorrhage.  The  value  of  the  treatment  cannot  be 
estimated  accurately,  owing  to  the  tendency  to  spontaneous  arrest  always 
present  in  these  hemorrhages  ;  but  the  results,  while  not  decisive,  do 
not  appear  very  encouraging. 

Another  treatment  of  aneurism  and  haemorrhage  of  recent  introduc- 
tion is  GELATINE  administered  by  the  mouth  or  hypodermically  (100 
c.c.  of  a  1—5  per  cent,  solution).  This  is  based  on  a  series  of  experiments 


570  INORGANIC  SALTS,   ACIDS  AND  BASES. 

which  seemed  to  indicate  that  the  coagulation  of  the  blood  is  hastened 
by  gelatine,  but  which  have  not  been  confirmed  by  later  investigators^ 
who  have  found,  that  while  the  blood  sometimes  clots  more  rapidly  than 
usual  in  the  presence  of  gelatine,  as  a  general  rule  the  process  is  nol 
changed  in  rate.  Gelatine  has  been  used  very  extensively  in  the  lasi 
few  years,  and  some  clinicians  report  favorable  results,  but  in  the 
hands  of  others  it  has  failed  to  influence  the  course  of  the  disease. 
Aneurism  of  the  aorta,  haemoptysis,  gastric,  intestinal,  renal,  and  uter- 
ine bleeding  have  all  been  treated  with  gelatine  with  very  doubtful 
benefit.  In  some  cases  gelatine  has  proved  the  channel  of  infection  by 
tetanus.  It  has  been  applied  to  still  local  haemorrhage  from  the 
mouth  and  nose,  but  has  been  supplanted  here  by  adrenaline. 

Gelatinum  (U.  S.  P.),  purified  gelatine.  Gelatinum  Glycerinatum  (U.  S.  P.), 
gelatine  impregnated  with  an  equal  weight  of  glycerin. 

PREPARATIONS. 

Calcii  Chloridum  (U.  S.  P.,  B.  P.)  (CaCl2),  a  white  salt  with  a  sharp,  saline 
taste,  very  deliquescent  and  soluble  in  water.  0.3-1  G.  (5-15  grs  ). 

Calcium  chloride  is  the  salt  which  gives  the  least  complicated  calcium  ac- 
tion, and  is  consequently  seldom  used,  because,  as  has  been  explained,  the 
calcium  ion  is  of  comparatively  little  service  in  therapeutics.  It  has  a  strong 
attraction  for  water  and  is  therefore  more  irritant  than  the  other  chlorides 
of  the  alkalies  and  alkaline  earths,  and  ought  to  be  prescribed  only  in  dilute 
solution.  It  is  absorbed  with  great  difficulty,  and  has  been  suggested  in  the 
treatment  of  some  forms  of  dyspepsia  and  in  haemorrhage. 

Calx  (U.  S.  P.,  B.  P.)  (CaO),  unslaked  lime,  is  a  corrosive  and  disinfectant, 
and  is  changed  at  once  to  the  hydrate  in  the  presence  of  water.  It  differs 
from  the  caustic  alkalies  in  the  insolubility  of  its  hydrate,  which  therefore 
fails  to  penetrate  deeply  and  does  not  spread  so  widely  as  potassium  and 
sodium  hydrates.  It  is  seldom  employed  alone  as  a  corrosive,  but  mixed 
with  potassium  hydrate  as  Vienna  paste  (Potassa  cum  Calce,  U.  S.  P.)  has 
had  some  popularity. 

It  is  used  as  a  disinfectant  where  large  quantities  of  organic  matter  have 
to  be  rendered  harmless,  as  in  epidemics,  on  battle  fields  and  in  the  dejec- 
tions of  large  hospitals.  It  ought  to  be  mixed  with  the  matter  to  be  disin- 
fected, as  thoroughly  as  possible.  Lime  possesses  the  advantage  over  other 
disinfectants  of  being  cheap  and  easily  procurable  in  large  quantities. 

Calcii  Hydras  (B.  P.),  slaked  lime  (Ca(HO)2),  may  also  be  used  as  a  disin- 
fectant. 

LIQUOR  C ALOIS  (U.  S.  P.,  B.  P.),  lime  water,  is  a  saturated  solution  of 
calcium  hydrate  or  slaked  lime  and  contains  about  0.17  G.  in  100  c.c.  (£  gr. 
in  1  oz.  B.  P.).  It  is  a  clear  fluid  with  a  saline  and  feebly  caustic  taste. 
30-100  c.c.  (1-4  fl.  oz.). 

SYRUPUS  CALCIS  (U.  S.  P.),  LIQUOR  CALCIS  SACCHARATUS  (B.  P.),  syrup 
of  lime,  contains  calcium  hydrate  kept  in  solution  in  water  by  sugar,  with 
which  it  is  probably  combined  chemically.  The  amount  of  lime  contained 
varies  greatly,  but  is  much  larger  than  in  lime  water.  The  B.  P.  prepara- 
tion is  said  to  contain  nearly  2  per  cent,  by  weight,  or  8  grs.  to  the  oz.  1-4 
c.c.  (15-60  mins.). 

LINIMENTUM  CALCIS  (U.  S.  P.,  B.  P.),  lime  liniment,  or  Carron  oil,  con- 
tains equal  parts  of  lime  water  and  olive  or  linseed  oil. 

These  preparations  owe  their  activity  chiefly  to  their  alkalinity  and 
not  to  the  calcium,  but  differ  from  the  hydrates  of  the  alkalies  in  their 
insolubility  and  in  their  slow  absorption.  Lime  water  and  the  syrup 


CALCIUM.  571 

are  slightly  caustic,  more  especially  the  latter,  and  tend  to  neutralize 
the  gastric  juice.  They  have  an  astringent  effect  in  the  intestine 
which  has  not  yet  been  explained,  but  is  probably  due  to  their  forming 
an  insoluble  compound  with  the  surface  proteids,  in  the  same  way  as 
tannic  acid,  or  to  their  being  deposited  as  the  carbonate  or  phosphate 
and  thus  protecting  the  epithelium  from  irritation.  Lime  water  is 
used  in  some  dyspeptic  conditions,  especially  in  vomiting.  It  is  often 
added  to  milk  in  intestinal  irritation  in  children  and  in  typhoid  fever, 
as  it  is  found  that  milk  thus  treated  coagulates  in  finer  particles  than 
when  given  alone,  and  is  better  digested  and  less  liable  to  disturb  the 
intestine.  Lime  water  or  syrup  of  lime  is  also  used  as  an  intestinal 
astringent  in  diarrhoea,  especially  in  children.  As  an  antacid  in  the 
stomach,  lime  is  .inferior  to  magnesia  and  other  alkalies,  because  it 
tends  to  delay  the  evacuation  of  the  contents.  Lime  water  has  been 
used  in  rickets,  which  seems  singularly  irrational,  for  cows'  milk  con- 
tains a  somewhat  higher  percentage  of  lime.  It  has  also  been  sprayed 
against  the  false  membrane  of  diphtheria,  which  it  is  said  to  dissolve. 
Lime  water  is  not  applicable  in  cases  of  acid  poisoning,  as  it  contains 
much  too  little  of  the  base  to  be  serviceable,  but  the  syrup  may  be 
used,  or  lime  shaken  up  with  water  (milk  of  lime).  The  treatment 
with  lime  is  specially  indicated  in  cases  of  oxalate  poisoning. 

Lime  water  has  been  used  externally  as  a  protective,  mildly  astrin- 
gent application  to  ulcers,  and  the  lime  liniment  has  been  largely  used 
in  the  treatment  of  burns.  It  derives  its  name  of  Carron  oil  from 
having  been  used  for  this  purpose  in  the  iron  works  at  Carron. 

Calcii  Carbonas  Pr&cipitatus  (U.  S.  P.,  B.  P.),  precipitated  chalk  (CaCO3). 
1-4  G.  (15-60  grs.). 

Greta  Prssparata  (U.  S.  P.,  B.  P.),  prepared  chalk,  chalk  purified  by 
washing  and  suspension  in  water  (CaCO3).  1-4  G.  (15-60  grs.). 

PULVIS  CRET.E  COMPOSITUS  (U.  S.  P.),  a  mixture  of  prepared  chalk,  sugar 
and  acacia.  5-10  G.  (1-2  drs.). 

PULVIS  CRET.E  AROMATICUS  (B.  P.),  aromatic  chalk  powder,  contains 
chalk  along  with  sugar  and  a  number  of  carminatives  belonging  to  the  group 
of  volatile  oils.  10-60  grs. 

PULVIS  CRET^;  AROMATICUS  CUM  OPIO  (B.  P.)  is  a  mixture  of  39  parts 
of  the  aromatic  powder  with  one  of  opium,  and  therefore  contains  2J  per 
cent,  of  opium.  10-40  grs. 

MISTURA  CRET^:  (U.  S.  P.),  chalk  mixture,  is  chalk  suspended  in  water 
by  means  of  gums.  15-30  c.c.  (J-l  fl.  oz.). 

The  preparations  of  the  carbonate  of  lime  are  used  as  antacids  in 
hyperacidity  of  the  stomach,  especially  when  this  is  combined  with 
a  tendency  to  diarrhoea.  The  mixture  or  the  aromatic  powder  B.  P., 
is  the  form  generally  used,  and  may  be  prescribed  with  opium  or  with 
other  astringents.  Chalk  has  also  been  used  in  rickets. 

Externally,  prepared  chalk  is  used  as  a  powder  to  protect  irritated 
parts  of  the  skin  and  occasionally  in  ulceration  ;  it  is  the  chief  in- 
gredient in  most  tooth  powders.  In  older  treatises  on  therapeutics, 
great  virtues  are  ascribed  to  various  natural  objects  which  are  com- 
posed for  the  main  part  of  chalk  or  other  salts  of  lime,  and  among 


572  INORGANIC  SALTS,  ACIDS  AND  BASES. 

which  burned  bones,  coral,  coralline,  and  cuttlefish  bone  may  be  men- 
tioned. 

Calcii  Phosphas  Prsecipitatus  (U.  S.  P.),  Calcii  Phosphas  (B.  P.)  (Ca3(PO4)2), 
a  white  insoluble  powder.  0.3-1  G.  (5-15  grs.). 

Syrupus  Calcii  Lactophosphatis  (U.  S.  P.,  B.  P.),  a  preparation  in  which  a 
soluble  double  salt  of  lime  is  contained  in  solution.  2-4  c.c.  (J-l  fl.  dr.). 

A  glycerophosphate  of  calcium  has  also  been  advised  recently.  These 
phosphate  preparations  have  been  used  in  rickets  and  osteomalacia,  and 
in  phthisis  and  other  tubercular  diseases,  but  the  best  authorities  are  agreed 
that  lime  salts  are  of  no  value  in  rickets  and  osteomalacia  (see  page  573), 
and  experience  with  them  in  tubercular  conditions  is  not  more  encouraging. 

Calcii  Bromidum  (U.  S.  P.)  (CaBr2)  has  been  used  as  a  substitute  for  the 
more  commonly  used  bromide  of  potassium,  and  is  administered  in  the  same 
dose.  It  is  more  slowly  absorbed  and  therefore  inferior  to  the  alkaline  bro- 
mides, and  is  entirely  superfluous. 

Calcii  Sulphas  Exsiccatus  (U.  S.  P.).  — Dried  calcium  sulphate  or  dried  gyp- 
sum contains  95  per  cent,  of  sulphate  of  calcium  (CaSO4)  and  5  per  cent,  of 
water.  It  is  used  exclusively  to  form  immovable  bandages  in  surgery  (plas- 
ter of  Paris  bandages). 

BIBLIOGRAPHY. 

See  Oxalates  and  Sodium  Chloride. 

Jankau.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix.,  p.  237. 

Raudnitz.     Ibid.,  xxxi.,  p.  343. 

Abel  u.  Muirhead.     Ibid.,  xxxi.,  p.  15. 

Radel     Ibid.,  xxxiii.,  pp.  79,  90. 

Rey.     Ibid.,  xxxv.,  p.  295.     Deutsch.  med.  Woch.,  1895,  p.  569. 

Brubacher.     Zts.  f.  BioL,  N.  F.,  ix.,  p.  516. 

F.  Voit.     Ibid.,  xi.,  p.  325. 

Weiske.     Ibid.,  xiii.,  p.  421. 

Ringer.     Journ.  of  Physiol.,  iii.-xvi. 

Howell  (and  pupils).  Ibid.,  xiv.,  p.  198  ;  xvi.,  p.  476.  Amer.  Journ.  of  Phys.,  v., 
p.  338  ;  vi.,  p.  181. 

Loeb,  Lingle,  Lillie,  Moore.  Amer.  Journ.  of  Phys.,  iv.,  p.  265  ;  v.,  pp.  56,  87, 
362 ;  vi.,  p.  411. 

Loew.     Ein  natiirliches  System  der  Giftwirkungen,  1893,  p.  33. 

Kitasato.     Zts.  f.  Hygiene,  iii.,  p.  404. 

Pfuhl.     Ibid.,  vi.,  p.  97. 

BineL     Comptes  rendus  d.  1'Acad.  de  Science,  cxv.,  p.  251. 

Bayer.     Med.  News,  1886,  ii.,  p.  253. 

Vierordt.     Nothnagel's  Specielle  Pathologic  und  Therapie,  vii. 

Hammarsten.     Ztschr.  f.  phys.  Chem.,  xxii.,  p.  333. 

Strauss.     Ztschr.  f.  klin.  Med.,  xxxi.,  p.  493. 

Miwa  u.  Stoeltzner.     Ziegler's  Beitriige  zu  Path.,  xxiv.,  p.  578. 

XX.     BARIUM   AND   STRONTIUM. 

Barium  is  the  most  poisonous  of  the  three  common  alkaline  earths,  but 
resembles  the  others  in  penetrating  with  difficulty  into  the  epithelium  of  the 
alimentary  canal,  and  is  therefore  absorbed  very  slowly.  It  has  a  charac- 
teristic action  on  many  forms  of  muscular  tissue,  resembling  closely  that  of 
veratrine,  and  the  contraction  of  the  frog's  muscle  under  barium  is  thus 
stronger  than  normally,  and  is  very  greatly  prolonged.  The  frog's  heart 
beats  more  strongly,  but  more  slowly  from  a  similar  action  on  the  muscle 
fibres,  and  the  walls  of  the  stomach  and  intestine  are  thrown  into  violent 
contraction  from  the  action  of  the  metal  on  the  unstriated  muscle  fibre. 
There  is  some  question  as  to  whether  the  central  nervous  system  is  acted  on 
in  the  frog,  but  in  the  mammal  barium  salts  injected  intravenously  cause 
violent  tonic  and  clonic  spasms,  from  their  stimulating  the  spinal  cord  and 
medulla  oblongata.  The  action  on  the  alimentary  canal  induces  vomiting 
and  purging  with  very  active  peristalsis.  The  heart  is  accelerated,  and  the 


SULPHIDES  AND  SULPHUR.  573 

blood-pressure  is  enormously  increased  at  first,  and  then  undergoes  slow 
undulations  for  gome  time.  The  increased  tension  may  be  due  to  the  cardiac 
action  in  part,  but  is  chiefly  to  be  ascribed  to  a  very  marked  contraction  of 
the  muscular  walls  of  the  vessels.  The  frog's  heart  eventually  assumes  an 
irregular  peristaltic  form  of  contraction  and  ceases  in  systole,  as  in  digitalis 
poisoning,  and  the  changes  in  the  mammalian  heart  also  resemble  those 
caused  by  this  series.  Barium  in  sufficient  quantities  finally  paralyzes  the 
central  nervous  system.  In  fatal  poisoning  in  animals,  haemorrhages  have 
been  found  in  the  stomach,  intestine,  kidney  and  other  organs. 

Barium  is  quite  incapable  of  replacing  calcium  in  its  relations  to  living 
matter,  and  accordingly  chloride  of  sodium  solutions  to  which  barium  chlo- 
ride has  been  added  do  not  tend  to  keep  the  frog's  heart  active  as  do  those 
containing  lime.  Some  authors  hold  that  barium  can  replace  calcium  to  an 
imperfect  degree  in  the  coagulation  of  the  blood,  but  this  is  denied  by  others. 
Potassium  salts  tend  to  neutralize  the  effect  of  barium  on  the  heart  and  mus- 
cles, the  relation  resembling  that  which  they  bear  to  lime. 

Barium  is  absorbed  slowly  from  the  intestine,  and  is  found  to  be  stored  in 
the  bones  to  some  extent,  and  to  be  excreted  in  the  urine  and  probably  in 
the  bowel. 

It  has  been  suggested  as  a  treatment  for  different  forms  of  tremor,  but  has 
seldom  been  used  in  practical  therapeutics. 

BIBLIOGRAPHY. 

Boehm,     Arch.  f.  exp.  Path.  u.  Pharm.,  iii. ,  p.  216. 

Neumann.     Pfliiger's  Arch.,  xxxvi.,  p.  576. 

Bruntonand  Cash.     Phil.  Trans,  of  Roy.  Soc.,  1884,  i.,  p.  223. 

Binet.     Comptes  rend.  d.  PAcad.,  cxv.,  £.  251. 

See  also  Bibliography  of  Calcium,  Potassium,  Rubidium  and  Caesium. 

Strontium  is  a  comparatively  inert  substance  even  when  injected  directly 
into  the  blood,  resembling  calcium  in  its  action  in  the  body  as  far  as  is 
known,  but  being  even  less  poisonous.  It  contracts  the  muscles  somewhat, 
tends  to  lessen  the  dilation  of  the  heart,  and  prolongs  the  contraction  of 
muscle,  though  only  to  a  slight  extent.  It  is  absorbed  very  slowly  from  the 
intestine  like  the  other  alkaline  earths,  find  is  deposited  in  small  quantities 
in  the  bones  of  growing  animals,  especially  when  there  is  a  deficiency  of  lime 
in  the  food.  It  is  excreted  in  small  quantities  by  the  urine,  but  mainly 
by  the  bowel.  Strontium  salts  have  been  used  to  a  limited  extent  in  thera- 
peutics, not  for  the  effect  of  the  strontium  ion,  but  for  the  bromide,  iodide 
or  salicylate  effects  of  its  salts.  In  view  of  the  fact  that  the  strontium  salts 
are  more  slowly  absorbed  than  the  corresponding  ones  of  sodium  and  potas- 
sium, there  would  seem  to  be  good  grounds  for  abandoning  their  use. 

PREPARATIONS. 

U.  S.  P.  —  Sirontii  Bromidum  (SrBr2  +  6H2O),  1-4  G.  (30-60  grs.). 
Strontii  lodidum  (SrI2  +  6H2O),  0.3-1  G.  (5-15  grs.). 
Strontii  Lactas  (Sr(C3H.O3)2  -f  3H2O),  1-2  G.  (15-30  grs.). 

BIBLIOGRAPHY. 

See  Calcium,  Barium. 

Wood.     Amer.  Journ.  of  Physiol.,  i.,  p.  83. 

Mendel  and  Thacher.     Ibid.,  xi.,  p.  5. 

XXI.     SULPHIDES   AND   SULPHUR. 

The  ordinary  sulphides  of  the  alkalies  are  of  little  importance  in* 
themselves,  as  they  are  seldom  used  in  therapeutics.     The  eifect  of 
hydrosulphuric  acid,  however,  apart  from  its  local  irritant  action,  is  due 


574  INORGANIC  SALTS,  ACIDS  AND  JBASES. 

to  the  sulphide  which  it  forms  in  the  blood,  and  the  study  of  this 
powerful  poison  therefore  involves  a  preliminary  examination  of  the 
effects  of  the  sulphides.  Again,  sulphur  is  in  itself  inert,  but  is 
changed  to  sulphides  and  hydrosulphuric  acid  in  the  alimentary  canal, 
and  the  effects  induced  by  its  administration  are  due  to  these  bodies, 
and  not  to  the  original  element. 

Action.  —  The  sulphides  are  very  weak  salts,  for  even  carbonic  acid  is 
capable  of  liberating  hydrosulphuric  acid,  and  wherever  they  come  in  con- 
tact with  it  in  quantity,  there  is  a  tendency  to  form  free  acid,  which  acts  as 
a  powerful  local  irritant ;  it  is  not  impossible  that  the  sulphides  have  an 
irritant  effect  of  themselves  in  addition  to  that  of  the  hydrosulphuric  acid. 
The  sulphides  accordingly  act  as  irritants  in  the  stomach  and  bowel,  and  in 
the  latter  induce  increased  peristalsis  and  purgation.  When  injected  sub- 
cutaneously  in  the  frog,  sodium  sulphide  causes  a  narcotic  condition  from 
depression  of  the  central  nervous  system,  and  in  sufficient  quantities  weakens 
the  skeletal  muscle  and  the  heart,  which  continues  to  beat  after  complete 
paralysis  has  been  obtained,  but  eventually  ceases  in  diastole.  Harnack  has 
recently  shown  that  after  the  narcosis  has  lasted  for  some  time,  a  new  con- 
dition follows,  if  only  small  quantities  have  been  given,  and  especially  if  the 
frog  is  healthy  and  is  kept  cool.  This  consists  in  an  enormous  increase  in 
the  reflex  irritability,  which  induces  convulsions  resembling  those  of  strych- 
nine poisoning  in  their  general  character,  but  differing  from  them  in  lasting 
continuously  for  weeks  or  even  months  at  a  time.  The  animal  lies  in  an  ex- 
tended and  tense  condition  throughout,  and  passes  into  complete  opisthotonos 
on  being  touched. 

Sulphides  injected  intravenously  in  mammals  induce  violent  convulsions, 
which  seem  to  be  of  cerebral  origin,  for  they  do  not  occur  in  the  hind  limbs 
when  the  spinal  cord  is  cut.  The  respiration  is  at  first  accelerated  and  latei 
dyspnceic  and  finally  ceases,  this  along  with  the  paralysis  of  the  vaso-motoi 
centre  being  the  cause  of  death.  The  heart  does  not  seem  to  be  seriously 
affected  except  indirectly  through  the  failure  of  the  respiration  and  the  fall 
of  the  blood-pressure. 

Sulphide  solutions  added  to  drawn  blood  reduce  the  oxyhsemoglobin  at 
once,  and  give  the  blood  a  dark  venous  color.  At  the  same  time  a  compound 
of  sulphide  and  haemoglobin  is  formed,  the  chemistry  of  which  is  still  very 
obscure,  but  which  would  seem  to  be  more  nearly  related  to  methsemoglobin 
than  to  haemoglobin.  It  is  known  as  sulpho-hsemoglobin  or  as  sulpho-met- 
hsemoglobin,  and  gives  the  blood  a  greenish  color  when  a  thin  layer  is  ex- 
amined, while  a  thicker  layer  is  dark  red-brown.  This  sulpho-hsemoglobin 
possesses  a  characteristic  spectrum,  marked  by  a  dark  line  in  the  red  to  the 
left  of  the  D  line.  Larger  quantities  give  an  olive-green  color  to  the  blood, 
and  the  spectrum  of  sulpho-hsemoglobin  disappears.  When  sulphides  are 
injected  into  frogs,  and  more  especially  when  sulphuretted  hydrogen  is  in- 
haled, the  blood  gives  the  characteristic  spectrum  during  life,  but  this  does 
not  seem  to  be  the  case  in  mammals,  although  sulpho-hsemoglobin  is  formed 
soon  after  death.  The  blood  changes  are  not  the  cause  of  death  in  poison- 
ing, as  was  formerly  supposed,  but  the  direct  action  of  the  sulphides  on  the 
central  nervous  system. 

Sulphides  absorbed  into  the  blood  are  rapidly  oxidized,  and  are  excreted  in 
the  urine  in  the  form  of  sulphates  and  of  organic  sulphur  compounds  of  un- 
known constitution.  Small  quantities  escape  by  the  lungs,  and  give  the 
breath  the  disagreeable  odor  of  sulphuretted  hydrogen,  and  according  to 
some  authorities,  some  is  excreted  in  this  form  in  the  perspiration. 

The  sulphides  dissolve  the  horny  epidermis  and  hair  very  readily  when 
they  are  applied  to  the  skin.  If  the  application  is  continued,  some  irritation 
and  redness  is  produced. 


SULPHIDES  AND  SULPHUR.  575 

Hydrosulphuric  Acid  (sulphuretted  hydrogen,  hydrogen  sulphide  (H?S)) 
differs  from  the  sulphides  in  being  a  gas,  and  in  its  strong  irritant  properties, 
which  it  shares  with  other  acids  (see  page  555).  It  has  not  infrequently 
given  rise  to  poisoning,  as  it  is  formed  in  large  quantities  in  the  course  of  the 
putrefaction  of  sulphur  compounds,  such  as  proteids.  Sewer  gas  often  con- 
tains it  in  quantity,  and  workmen  employed  in  cleansing  sewers  or  cesspools 
have  often  suffered  from  its  effects.  When  inhaled  in  concentrated  form  it 
is  almost  immediately  fatal,  the  patient  losing  consciousness  at  once,  and  the 
respiration  ceasing  after  a  few  seconds.  In  smaller  quantities  it  causes  im- 
mediate unconsciousness,  lasting  for  several  hours  and  then  passing  into  fatal 
coma,  which  is  often  interrupted  by  violent  convulsions.  In  both  of  these 
forms  the  symptoms  are  due  to  the  direct  action  of  the  sulphides  on  the  brain 
and  medulla  oblongata.  Persons  exposed  to  a  very  dilute  vapor  of  sulphur- 
etted hydrogen  suffer  from  local  irritation  of  the  eyes,  nose  and  throat,  indi- 
cated by  pain  and  congestion  of  the  conjunctiva,  sneezing,  dryness  and  sore- 
ness of  the  mouth  and  throat,  and  a  reflex  increase  in  the  secretion  of  tears, 
saliva  and  mucus.  Headache,  dulness,  giddiness  and  loss  of  energy  are  com- 
plained of;  the  symptoms  frequently  appear  only  some  time  after  the  ex- 
posure to  the  poison.  According  to  Lehmann,  death  in  animals  exposed  to 
these  dilute  fumes  is  due  in  part  to  oedema  of  the  lungs  caused  by  the  local 
irritant  action.  He  fouad  that  one  part  of  hydrosulphuric  acid  in  5,000  of 
air  was  sufficient  to  induce  symptoms  in  man,  and  that  an  atmosphere  con- 
taining one  part  in  2,000  could  be  respired  for  only  a  short  time,  and  gave 
rise  to  alarming  symptoms  ;  he  supposes  that  about  one  part  of  hydrosul- 
phuric acid  in  1,000  parts  of  air  is  sufficient  to  poison  man  fatally  in  a  very 
short  time. 

The  poisonous  effect  of  sulphuretted  hydrogen  is  due  in  part  to  its  local 
irritant  action,  in  part  to  its  directly  affecting  the  central  nervous  system. 
The  changes  in  the  blood  occur  during  life  only  after  very  concentrated  gas 
is  inhaled,  although  they  may  indicate  the  poison  after  death  from  more 
dilute  vapor,  for  the  tissues  in  general  tend  to  assume  a  green  color  sooner 
after  hydrosulphuric  acid  poisoning  than  in  the  course  of  ordinary  putrefaction. 

Hydrogen  sulphide  is  destructive  to  most  forms  of  life,  even  when  present 
in  comparatively  small  amount.  Even  the  microbes  of  putrefaction,  which 
produce  it  themselves,  are  eventually  killed  by  this  gas,  unless  it  escapes 
freely. 

PREPARATIONS. 

Potassa  Sulphurata  (B.  P. ),  liver  of  sulphur  (Hepar  Sulphuris),  is  a  mixture 
of  polysulphides  and  thiosulphates,  often  containing  sulphate  of  potassium.  The 
greater  part  is  formed  of  potassium  trisulphide  (K2S3)  and  of  potassium  thio- 
sulphate  (K2S2O3).  It  is  soluble  in  water  and  possesses  an  unpleasant  saline 
taste,  and  an  odor  of  hydrogen  sulphide,  which  is  formed  by  its  decomposition 
in  water. 

Calx  Sulphurata  (U.  S.  P.,  B.  P.),  sulphurated  lime,  is  another  impure 
preparation  containing  at  least  60  per  cent,  of  calcium  monosulphide  (CaS) 
(50  per  cent.  B.  P.),  with  some  calcium  sulphate  and  charcoal.  It  forms  a 
grayish  powder,  insoluble  in  water,  and  gives  off  hydrogen  sulphide.  0.015 
-0.06  G.  (J-l  gr.). 

These  preparations  are  seldom  used  internally,  and,  in  fact,  the  sulphur- 
ated potassium  has  been  found  to  be  a  dangerous  poison,  from  the  hydrogen 
sulphide  given  off  .by  it  in  the  bowel  acting  both  locally  and  after  absorption. 

Sulphurated  potassium  is  used  to  a  very  limited  extent  as  an  external  appli- 
cation in  certain  skin  diseases,  particularly  in  acne,  and  to  destroy  skin 
parasites,  such  as  that  of  scabies.  It  is  used  as  an  ointment  (1  part  to  10 
parts),  and  is  somewhat  irritant. 

Sulphurated  lime  is  used  occasionally  to  remove  hair  and  horny  excres- 
cences, both  of  which  it  renders  soft  and  gelatinous,  but  its  frequent  use  is 
liable  to  cause  irritation. 


576  INORGANIC  SALTS,   ACIDS  AND  BASES. 

Hydrogen  sulphide  has  been  used  in  the  treatment  of  pulmonary  phthisis, 
the  gas  being  applied  by  the  rectum,  but  the  treatment  was  followed  in  sev- 
eral cases  by  serious  symptoms  of  poisoning,  and  has  not  been  shown  to  be 
beneficial.  Very  small  quantities  only  escape  by  the  lungs. 

Many  mineral  springs  contain  hydrogen  sulphide  in  small  amount,  and 
these  have  obtained  wide  celebrity  in  the  treatment  of  various  chronic  res- 
piratory and  skin  diseases  and  in  syphilis,  gout,  rheumatism  and  chronic 
metallic  poisoning  (lead,  mercury).  Most  of  these  springs  are  hot,  and  it  is 
open  to  question  whether  the  small  amount  of  the  gas  contained  in  the 
water  is  of  any  efficacy,  and  whether  the  heat  of  the  water  and  the  hygienic 
conditions  are  not  the  true  cause  of  the  improvement  observed  in  these  cases, 
Sulphur  baths  are  also  formed  artificially  by  the  addition  of  sulphuratec 
potassium  (2-8  oz.)  to  an  ordinary  hot  bath  ;  a  small  quantity  of  acid  is  some- 
times added,  in  order  to  free  the  hydrogen  sulphide  more  rapidly. 

Sulphur  is  in  itself  an  inert  body,  but  while  much  the  greater  portior 
escapes  in  the  stools  unchanged  when  it  is  swallowed,  some  of  it  forms 
sulphides  in  the  mucous  membrane  of  the  intestine,  and  these  cause 
irritation,  increased  peristalsis,  and  mild  purgation  ;  in  large  quantities 
it  has  caused,  in  some  instances,  more  severe  symptoms  with  bloody  evac- 
uations. The  sulphides  form  some  hydrogen  sulphide,  which  gives 
rise  to  eructation.  Some  10-20  per  cent,  of  the  sulphur  taken  by  the 
mouth  is  absorbed  as  sulphide,  which  is  excreted  to  a  small  extent  by  the 
lungs,  giving  the  characteristic  disagreeable  odor  to  the  breath,  and  tc 
a  mnch  larger  extent  by  the  urine  as  sulphates  and  in  organic  combi- 
nation. In  one  experiment,  Presch  found  the  urea  of  the  urine  con- 
siderably increased  (10  per  cent.)  under  sulphur,  and  Umbach  found 
it  increased  by  pure  calcium  sulphide  ;  whether,  as  this  would  suggest, 
the  sulphides  augment  the  nitrogenous  waste  as  a  general  rule,  can  only 
be  determined  by  further  experiment. 

Applied  to  the  skin  in  ointment,  sulphur  appears  to  be  formed  in 
part  to  sulphide,  particularly  if  some  alkali  be  added. 

PREPARATIONS. 

Sulphur  Sublimatum  (U.  S.  P.,  B.  P.),  Flowers  of  Sulphur,  sublimed  sul- 
phur. 

Sulphur  Lotum  (U.  S.  P.),  washed  Flowers  of  Sulphur,  is  prepared  bj 
washing  the  sublimed  sulphur  with  water  and  ammonia.  These  prepara 
tions  form  fine  yellow  powders  insoluble  in  water  and  very  slightly  soluble 
in  alcohol.  1-4  G.  (15-60  grs.)  in  powder  or  sometimes  in  tablets. 

Sulphur  Prsecipitatum  (U.  S.  P.,  B.  P.),  Milk  of  Sulphur,  is  prepared  fron 
sulphide  of  calcium  by  precipitation  and  forms  a  fine,  almost  white  powdei 
without  odor  or  taste,  insoluble  in  water,  and  only  very  slightly  soluble  ir 
alcohol.  1-4  G.  (15-60  grs.). 

Unguentum  Sulphuris  (U.  S.  P.,  B.  P.),  formed  from  sublimed  sulphur, 
which  is  also  contained  in  the  Compound  Liquorice  Powder. 

Trochiscus  Sulphuris  (B.  P.)  contains  5  grs.  of  sulphur. 

Confectio  Sulphuris  (B.  P.),  60-120  grs. 

Thilanin  (non-official)  is  a  mixture  of  lanolin  and  sulphur  containing  aboui 
3  per  cent,  of  the  latter,  and  has  been  proposed  as  a  substitute  for  the  oint 
ment. 

Crude  sublimed  sulphur  often  contains  arsenic  and  other  impurities,  anc 
ought  not  to  be  used  in  therapeutics.  The  milk  of  sulphur  is  in  a  finei 
state  of  division  than  the  flowers,  and  is  said  to  be  a  somewhat  more  active 
aperient. 


SULPHIDES  AND  SULPHUR.  577 

SulphuT  is  used  as  an  aperient  powder,  and  may  be  added  to  rhu- 
barb or  magnesia  for  this  purpose  ;  it  causes  a  soft,  formed  stool,  and 
seldom  induces  more  than  one  evacuation.  It  is  prescribed  for  chil- 
dren, and  in  cases  of  haemorrhoids,  in  which  it  is  often  very  beneficial, 
not  owing  to  any  specific  effect  on  the  haemorrhoids,  but  because  it 
renders  the  stool  softer  and  less  liable  to  cause  irritation  mechanically. 

Sulphur  has  been  advised  in  a  variety  of  constitutional  diseases  and 
in  chlorosis,  skin  and  joint  affections,  but  it  is  impossible  to  state  at 
present  whether  it  has  any  effect  in  these  apart  from  its  improving  the 
condition  of  the  intestine. 

Sulphur  ointment  has  been  used  in  some  skin  diseases,  particularly 
xn  scabies,  but  has  been  supplanted  to  a  large  extent  by  the  balsam  of 
Peru.  It  has  been  applied  in  powder  to  diphtheritic  membranes. 

BIBLIOGRAPHY  of  Sulphides  and  Sulphur. 

Kaufmann  u.  Rosenthal     Arch,  f .  Anat.  u.  Phys. ,  1865,  p.  659. 
Lewin.      Virchow's  Arch.,  Ixxiv.,  p.  220. 
Lehmann.     Arch.  f.  Hygiene,  xiv.,  p.  135. 
Pohl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxii.,  p.  1. 

Harnack.     Ibid.,  xxxiv.,  p.  156.     Ztschr.  f.  phys.  Chem.,  xxvi.,  p.  558. 
Regensburger.     Ztschr.  f.  Biol.,  xii.,  p.  479. 
Presch.     Virchow's  Arch.,  cxix.,  p.  148. 
Uschinsky.     Zts.  f.  phys.  Chem.,  xvii.,  p.  220. 
Binet.     Trav.  des  Lab.  de  Ther.  exp.  de  Geneve,  ii.,  p.  242. 
Umbach.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxi.,  p.  166. 
Meyer.     Ibid.,  xli.,  p.  325. 

Heffter.  Beitr.  z.  chem.  Phys.  u.  Path.,  v.,  p.  213.  Arch.  f.  exp.  Path.  u.  Pharm., 
li.,  p.  175. 

Thiosinamine. — Thiosinamine  (CS-NH2-NHC3H5)  has  recently  been  intro- 
duced into  therapeutics  in  the  treatment  of  scar  tissue  of  many  different  forms. 
It  is  a  comparatively  inactive  body  in  normal  tissues,  but  large  doses  in  animals 
induce  tremor,  vomiting,  weakness,  and  deep  sleep  with  slow,  deep  respiration. 
The  central  nervous  system  is  first  stimulated  and  then  depressed.  Fatal  doses 
in  animals  induce  oedema  of  the  lungs  and  hydrothorax,  and  in  frogs  anasarca  is 
generally  present.  Thiosinamine  forms  colorless,  bitter,  odorless  crystals  which 
are  readily  soluble  in  alcohol,  less  so  in  water.  It  is  used  to  induce  softening 
and  absorption  of  cicatricial  tissue  in  the  skin  and  internal  organs,  and  may  be 
applied  locally  as  a  10  per  cent,  plaster  or  ointment  to  the  skin,  but  is  much 
more  frequently  injected  hypodermically  in  15  percent,  solution  in  alcohol,  about 
1  c.c.  (15  mins.)  being  injected  each  day.  It  has  also  been  given  internally  in 
capsules.  Almost  every  form  of  cicatrix,  whether  following  acute  or  chronic 
inflammation  or  surgical  operation,  has  been  treated  with  thiosinamine,  and 
many  very  favorable  results  have  been  reported.  In  most  of  these  cases  there 
was  no  possibility  of  verifying  the  results  by  direct  observation,  but  more  satis- 
factory evidence  has  recently  been  adduced  in  cicatricial  conditions  in  the  eye,  in 
which  relief  was  obtained.  No  explanation  of  the  action  has  as  yet  been 
suggested. 

BIBLIOGRAPHY. 

Dollken.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvii.,  p.  321. 
Lewandowski.     Therap.  d.  Gegenwart,  1903,  p.  441. 
Suker.     Journ.  Amer.  Med.  Ass.,  Aug.  9,  1902.  . 
37 


578  INORGANIC  SALTS,  ACIDS  AND  BASES. 

XXII.     CHARCOAL. 

Charcoal,  like  spongy  platinum  and  other  porous  bodies,  possesses  the 
property  of  accumulating  gases  in  its  interstices  and  thus  ordinarily  contains 
considerable  quantities  of  oxygen.  When  brought  into  contact  with  decom- 
posing matter,  the  oxygen  is  released  and  hastens  the  oxidation  of  the  putre- 
fying mass,  while  the  gases  arising  from  the  bacterial  action  are  absorbed  by 
the  charcoal  which  thus  acts  as  a  deodorant.  It  has  no  direct  action  on  the 
microbes  of  putrefaction,  but  may  by  introducing  oxygen  favor  the  develop- 
ment of  the  aerobic  organisms  at  the  expense  of  the  anaerobic.  Besides 
gases,  charcoal  also  absorbs  many  colloid  bodies,  such  as  the  coloring  matter 
of  plants  and  proteids. 

Animal  charcoal  appears  to  possess  no  advantages  over  wood  charcoal, 
and  they  both  act  when  moist  almost  as  efficiently  as  in  the  dry  state. 

Charcoal  has  no  appreciable  effect  on  the  economy,  apart  from  its  lessen- 
ing the  eructation  of  gas  and  the  flatulence  in  some  cases.  It  passes  through 
the  stomach  and  intestine  unabsorbed,  and  may  in  rare  cases  cause  some 
mechanical  irritation  and  increased  movement.  Charcoal  given  in  a  state  of 
suspension  to  animals  is  said  to  have  been  found  in  the  epithelial  cells  of  the 
intestine  and  even  in  the  blood  vessels,  but  does  not  have  any  effect  attribut- 
able to  its  absorption  in  man.  (Wild.  Med.  Chronicle,  1896.) 

PREPARATIONS. 

Carbo  Animalis  (U.  S.  P.),  animal  charcoal,  bone-black,  prepared  from 
bone. 

Carbo  Animalis  Purificatus  (U.  S.  P.)  is  prepared  by  boiling  bone-black 
with  hydrochloric  acid  in  order  to  remove  the  lime  and  other  impurities. 

Carbo  Ligni  (U.  S.  P.,  B.  P.) — Charcoal  prepared  from  soft  wood  and 
finely  powdered. 

Charcoal  is  used  internally  to  remove  the  gases  in  flatulence  and  dyspep- 
sia, and  is  prescribed  in  powder  or  in  the  form  of  charcoal  lozenges.  It  may 
be  given  in  any  quantity,  but  is  most  commonly  prescribed  in  4-8  G.  (60- 
120  grs.)  doses.  It  is  employed  externally  as  a  deodorant  in  cases  of  foul 
ulcers,  cancerous  sores,  or  malodorous  secretions  from  any  source  ;  for  this 
purpose  it  is  added  to  poultices  or  used  dry  in  bags  of  fine  cloth. 

XXIII.    BORACIC  ACID  AND  BORAX. 

Boracic  or  boric  acid  (B(OH)3)  is  a  very  weak  acid,  and  it  is  doubt- 
ful whether  the  hydrogen  ions  or  acidity  play  any  part  in  its  action,  or 
whether  the  whole  is  not  to  be  referred  to  the  rest  of  the  molecule. 
The  ordinary  sodium  compound,  borax,  Na9B4O7,  is  stated  by  some 
authors  to  be  equally  active,  but  is  alkaline  in  reaction,  so  that  the 
exact  relative  importance  of  the  two  ions  of  boric  acid  cannot  be  de- 
termined. 

Action.  —  Boracic  acid  and  borax  are  only  feebly  toxic,  but  large 
quantities  taken  by  the  mouth  cause  gastric  and  intestinal  irritation,  as 
is  evidenced  by  vomiting  and  purging,  and  even  smaller  amounts  are 
said  to  act  as  mild  aperients  in  some  cases.  In  animals  muscular  weak- 
ness and  collapse,  and,  it  is  said,  nephritis  and  albuminuria  have  been 
elicited  by  the  injection  of  poisonous  doses.  Moderate  doses  are  with- 
out effect  on  the  metabolism/ but  larger  quantities  (5-10  G.  per  day  in 
dogs)  increase  the  nitrogen  excretion  in  the  urine.  In  ordinary  amounts 
borax  does  not  affect  the  digestion  and  assimilation  of  food,  but  larger 
doses  increase  the  bulk  of  the  fa3ces  by  retarding  the  absorption  of  the 


BORACIC  ACID  AND  BORAX.  579 

proteids  and  fats.1  Both  borax  and  boracic  acid  are  rapidly  absorbed 
by  the  bowel,  and  do  not  affect  the  intestinal  putrefaction. 

Boracic  acid  has  been  widely  used  as  an  antiseptic  dressing,  and  a 
number  of  cases  of  serious  poisoning  have  been  recorded  from  its  ab- 
sorption. The  symptoms  arose  in  part  from  the  alimentary  canal, 
uneasiness  in  the  abdomen,  vomiting,  diarrhoea,  dry  ness  of  the  throat 
and  difficulty  in  swallowing ;  sleeplessness,  great  muscular  weakness 
and  depression,  dimness  of  sight,  and  headache  were  also  complained 
of,  and  in  severe  cases  collapse  and  death  followed.  The  prolonged 
use  of  boracic  acid,  internally  or  externally,  has  repeatedly  led  to  scaly 
skin  diseases,  eczema,  psoriasis  and  alopecia.  Papular  eruptions  and 
local  cedemas  and  swelling  of  the  skin  appear,  and  a  dark  line  on  the 
gums,  similar  to  that  seen  in  lead  poisoning,  is  stated  to  occur  along 
with  irritation  of  the  mouth.  These  skin  affections  appear  also  when 
borax  is  used  in  large  quantities  as  an  antiseptic  dressing. 

Boracic  acid  and  borax  are  excreted  in  the  urine,  in  which  they 
appear  within  a  few  minutes  after  ingestion  ;  over  half  the  quantity 
taken  is  excreted  within  12  hours,  but  afterward  the  elimination 
proceeds  more  slowly,  so  that  traces  may  be  found  in  the  urine  for 
5  days  or  more.  It  is  sometimes  stated  that  the  urine  is  increased 
by  borax,  but  this  is  not  borne  out  by  experiment,  and  Chittenden  and 
Gies  found  it  actually  diminished  in  amount;  the  reaction  becomes 
alkaline  after  sufficient  amounts  of  borax,  as  after  any  other  alkaline 
preparation.  Boracic  acid  and  borax  have  some  antiseptic  power,  for  in 
2J  per  cent,  solution  almost  all  forms  of  bacilli  stop  growing;  but  they 
are  not  destroyed,  even  the  delicate  anthrax  bacilli  being  found  capable  of 
further  growth  after  exposure  to  a  4  per  cent,  solution  for  24  hours. 
Boracic  acid  is  therefore  valueless  as  a  disinfectant,  but  has  been  used 
as  an  antiseptic  dressing ;  it  has  the  advantage  over  many  other  anti- 
septics of  inducing  very  little  irritation  and  of  being  only  slightly 
poisonous,  but  experience  has  shown  that  it  cannot  be  used  with  im- 
punity in  very  large  quantities. 

PREPARATIONS. 

Acidum  Boricum  (U.  S.  P.,  B.  P.),  Boric  or  Boracic  Acid  (H3BO3),  color- 
less crystals,  with  a  faintly  bitter  taste,  soluble  to  about  four  per  cent,  in 
water,  more  so  in  alcohol  and  glycerin.  0.3-1  G.  (5-15  grs.). 

Glyceritum  Boroglycerini  (U.  S.  P.),  Glycerinum  Acidi  Borici  (B.  P.).  Boro- 
glycerin  is  a  compound  formed  by  heating  boric  acid  in  glycerin,  and  the 
official  glyceritum  or  glycerinum  contains  this  dissolved  in  glycerin,  about 
31  parts  of  boric  acid  being  used  to  form  100  parts. 

Liquor  Antisepticus  (U.  S.  P. ),  containing  2  per  cent,  of  boric  acid,  along  with 
benzoic  acid,  thymol,  eucalyptol,  and  oils  of  peppermint,  wintergreen  and  thyme. 

Unguentum  Acidi  Sorici  (B.  P.,  U.  S.  P.),  10  per  cent. 

Sodii  Boras  (U.  S.  P.),  Borax  (B.  P.),  Borax  (Xa2B4O7  +  10H2O)  forms 
colorless  crystals  with  a  sweetish  alkaline  taste.  It  is  soluble  in  water  (16 
parts)  to  which  it  gives  an  alkaline  reaction.  0.3-1.3  G.  (5-20  grs.). 

Glycerinum  Boracis  (B.  P.)  (1  in  6). 

Mel  Boracis  (B.  P.). 

1  The  body  weight  often  falls  under  borax  treatment,  and  this  has  been  attributed  to 
augmented  fat  destruction  by  Eost  and  Rubner,  who  state  that  a  corresponding  increase 
in  the  carbonic  acid  elimination  accompanies  it. 


580  INORGANIC  SALTS,   ACIDS  AND  BASES. 

Boracic  acid  has  been  used  as  a  surgical  antiseptic  in  solution  (four 
per  cent.),  ointment,  or  lint,  and  the  solution  of  the  acid  or  of  borax 
is  also  used  as  a  wash  in  aphthe  and  other  forms  of  irritation  of  the 
mouth.  Boracic  acid  solution  has  been  given  internally  in  dilute 
watery  solution  as  a  genito-urinary  disinfectant,  has  also  been  injected 
into  the  bladder,  and  is  frequently  used  in  ophthalmic  surgery,  as  be- 
ing less  irritant  to  the  eye  than  the  more  powerful  antiseptics.  In 
internal  medicine  the  acid  and  the  salt  have  been  used  in  epilepsy,  and 
also  in  the  hope  of  dissolving  uric  acid  calculi,  but  have  not  been 
shown  to  be  efficient  for  either  purpose.  Boracic  acid  and  borax  are 
sometimes  added  to  milk  or  other  food  as  preservatives,  and  it  has 
been  much  discussed  whether  the  habitual  use  of  such  preserved  foods 
is  likely  to  prove  deleterious  to  the  health.  The  general  result  of  the 
investigations  is  that  while  no  preservative  should  be  added  to  food 
unless  it  is  absolutely  unavoidable,  boric  acid  is  less  liable  to  derange 
the  health  than  most  other  preservatives.  Foods  preserved  with 
boracic  acid  should  not  be  used  by  delicate  individuals  or  by  children, 
however,  and  the  quantity  of  the  acid  used  must  be  strictly  limited. 

BIBLIOGRAPHY. 

Neumann,     Arch,  f.  exp.  Path.  u.  Pharm.,  xiv.,  p.  149. 

Forster.     Arch.  f.  Hygiene,  ii.,  p.  75. 

Rost  u.  Sonntag.     Arb.  a.  d.  Kais.  Gesundheitsamte,  xix.,  p.  110. 

He/ter.     Ibid.j  xix.,  p.  97. 

Fere,     Semaine  Medical,  1894. 

Chitienden  and  Gies.     Am.  Journ.  of  Phys.,  i.,  p.   1. 

Wild.     Lancet,  1899,  i.,  p.  23. 

Liebreich.     Vierteljahrsch.  f.  ger.  Med.,  1900,  xviii.,  p.  83. 

Lange.     Arch.  f.  Hygiene,  xl.,  p.  143. 

Kilter.     Ztschr.  f.  Hygiene,  xxxvii.,  p.  225. 

Tunnicliffe  and  Rosenheim.     Journ.  of  Hygiene,  i.,  p.  168. 

Vaughan  and  Veenboer.     Amer.  Medicine,  1902,  Mar.  15th. 

XXIV.     CARBONIC  ACID. 

Carbonic  acid  is  contained  in  considerable  quantity  in  many  thera- 
peutic preparations,  notably  in  the  effervescent  cathartics  and  antacids, 
and  also  in  many  beverages,  such  as  soda  water,  potash  water,  cham- 
pagne and  other  sparkling  wines.  In  some  of  these  it  is  formed  by 
the  action  of  an  acid  such  as  citric  or  tartaric  acid  on  carbonates,  in 
others  it  is  liberated  in  the  course  of  fermentation,  while  in  the  artifi- 
cial aerated  waters  it  is  forced  into  solution  under  high  pressure.  The 
last  are  therefore  simple  solutions  of  carbonic  acid,  while  in  the  others 
more  powerful  agencies  —  cathartic  salts  or  alcohol  —  are  contained  in 
addition. 

Carbonic  acid  has  a  weak  irritating  action  when  applied  in  quantity ; 
thus  in  baths  charged  with  carbonic  acid,  a  slight  reddening  of  the 
skin  has  been  observed,  and  some  irritation  and  prickling  of  denuded 
surfaces  is  produced ;  a  stream  of  carbonic  acid  directed  against  a 
wound  or  burn  causes  considerable  heat  arid  pain.  Pure  carbonic  acid 
gas  causes  spasm  of  the  glottis  when  inhaled,  and  even  when  it  is  much 


CARBONIC  ACID.  581 

diluted,  some  irritation  in  the  respiratory  passages  may  follow  at  first. 
Solutions  of  carbonic  acid  induce  reddening  of  the  mucous  membrane 
of  the  mouth  and  stomach,  and  are  very  rapidly  absorbed,  owing  to 
the  congestion  and  increased  blood  flow  in  the  stomach  wall  which 
follows  their  administration.  Much  of  the  carbonic  acid  is  thrown  up 
by  eructation,  but  some  of  it  is  absorbed  and  is  excreted  by  the  lungs. 
The  absorbed  acid  has  no  effect  on  the  organism,  but  the  slight  irrita- 
tion of  the  stomach  may  cause  increased  appetite  and  a  feeling  of  well- 
being.  The  rapid  absorption  of  the  water  in  which  it  is  dissolved  is 
followed  by  an  augmented  secretion  of  urine,  and  the  carbonic  acid 
waters  are  therefore  used  in  preference  to  ordinary  waters,  where  a 
rapid  flushing  of  the  tissues  and  a  profuse  secretion  of  urine  is  de- 
sired. In  addition,  the  slight  irritation  of  the  mouth  and  stomach 
renders  them  more  acceptable  than  ordinary  waters  in  fever  and  in 
other  diseases  accompanied  by  intense  thirst ;  a  mixture  of  milk  and 
aerated  water  is  often  very  grateful.  The  presence  of  carbonic  acid 
in  the  sparkling  wines  leads  to  the  rapid  absorption  of  the  alcohol 
also,  and  this  action  on  the  stomach  may  explain  their  being  more  ex- 
hilarating than  other  wines  containing  an  equal  amount  of  alcohol. 
The  slight  irritant  effect  of  carbonic  acid  in  the  stomach  has  proved 
of  benefit  in  some  forms  of  gastric  catarrh,  such  as  that  following 
alcoholic  excess.  Carbonic  acid  waters  are  also  useful  in  the  vomiting 
of  pregnancy  and  in  seasickness. 

The  prolonged  application  of  carbonic  acid  to  the  mucous  mem- 
branes leads  to  local  anaesthesia,  and  numbing  of  the  skin  is  also  stated 
to  occur  under  similar  treatment. 

Carbonic  acid  is  absorbed  from  all  the  mucous  membranes,  from  the 
skin  and  from  the  lungs.  The  gas  has  no  effect  after  absorption  ex- 
cept when  inhaled,  however,  as  when  absorbed  in  any  other  way  it 
is  at  once  excreted  by  the  lungs,  and  the  amount  absorbed  never  alters 
appreciably  the  normal  percentage  of  carbonic  acid  in  the  blood. 

When  carbonic  acid  is  inhaled  unmixed  with  oxygen,  it  induces  asphyxia, 
partly  from  a  specific  action  which  it  exerts  on  the  central  nervous  system, 
but  chiefly  from  the  absence  of  oxygen.  Its  effects  are  therefore  very 
similar  to  those  of  any  indifferent  gas,  such  as  hydrogen  or  nitrogen,  and 
the  symptoms  are  those  of  ordinary  asphyxia.  When,  however,  carbonic 
acid  is  inhaled  mixed  with  a  sufficient  amount  of  oxygen,  the  specific 
effects  of  the  gas  are  observed  without  any  asphyxia.  The  symptoms  are 
those  of  transient  stimulation  and  subsequent  depression  of  the  central 
nervous  system  and  heart.  The  first  stage  is  marked  by  a  very  short  period 
of  psychical  exaltation,  with  deep  respirations,  a  slight  rise  in  the  blood- 
pressure  and  a  moderately  slow  pulse.  Very  soon,  however,  unconscious- 
ness, loss  of  the  spontaneous  movements,  and  later  of  the  spinal  reflexes 
follow,  the  respiration  becomes  somewhat  slower  and  shallower,  the  pulse 
continues  slow  and  the  heart  is  weaker.  If  the  inhalation  be  continued  the 
respiration  fails,  the  heart  continuing  to  beat  for  a  short  time,  though  weakly. 
The  symptoms  of  the  first  stage  seem  to  be  due  to  a  direct  stimulant  action 
on  the  cerebrum  and  on  the  vagus,  vaso-motor  and  respiratory  centres,  while 
the  second  stage  resembles  that  induced  by  the  ordinary  anaesthetics,  and 
is  evidently  caused  by  depression  of  the  central  nervous  system  and  of  the 
heart  muscle.  In  fact  a  mixture  of  carbonic  acid  and  air  has  been  used  as 


582  INORGANIC  SALTS,  ACIDS  AND  BASES. 

an  anaesthetic  in  one  or  two  surgical  operations.  Death  from  carbonic  acic 
poisoning  is  not  preceded  by  convulsions,  those  observed  in  ordinary  as 
phyxia  being  due  to  the  absence  of  oxygen,  and  not  to  the  excess  of  car 
bonic  acid  ;  it  is  still  undecided  by  which  of  these  factors  the  increased  per 
istalsis  seen  in  suffocation  is  caused.  In  well  diluted  vapor  the  symptom 
of  exaltation  alone  are  observed,  no  anaesthesia  following. 

Carbonic  acid  in  excess  acts  as  a  poison  to  other  organs  besides  the  centra 
nervous  system  and  the  heart,  although  this  effect  is  not  seen  in  mammals 
Prog's  muscle  loses  its  irritability  rapidly,  the  ciliated  epithelium  cease 
movement,  and  the  motor  nerves,  after  a  short  period  of  increased  excita 
bility,  are  paralyzed  by  exposure  to  an  atmosphere  of  carbonic  acid.  Th 
blood  assumes  the  venous  color  when  shaken  with  the  gas,  and  prolongei 
contact  produces  acid  hsematin,  as  does  any  other  acid. 

Carbonic  acid  probably  acts  as  a  general  poison  to  the  protoplasm  in  mam 
mals,  apart  from  the  effects  on  the  central  nervous  system,  for  the  combustio: 
in  the  tissues  is  lessened  to  an  extraordinary  degree,  as  is  evidenced  by  th 
very  small  amount  of  oxygen  absorbed. 

Compressed  carbonic  acid  gas  absorbs  much  heat  in  expanding,  and 
stream  of  it  directed  against  the  skin  induces  intense  cold  and  might  there 
fore  be  used  to  induce  local  anesthesia.     (See  Ether,  page  182.) 

The  inhalation  of  diluted  carbonic  acid  has  been  recommended  in  variou 
pulmonary  affections,  such  as  phthisis  and  bronchitis,  but  is  of  very  doubl 
fill  benefit. 

Mineral  waters  containing  large  quantities  of  carbonic  acid  in  solution  ar 
often  recommended  as  baths  in  various  chronic  diseases,  such  as  rheumatism 
The  effects  may  be  due  to  the  carbonic  acid  in  part,  but  these  waters  als< 
contain  salts  in  solution. 

BIBLIOGRAPHY. 

P.  Bert.     Lemons  sur  la  Respiration.     Paris,  1870. 

Quincke.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii.,  p.  101. 

Eunge.     Ibid.,  x.,  p.  332. 

Friedldnder  u.  Herter.     Zts.  f.  phys.  Chem.,  ii.,  p.  99. 

Loewy.     Pfliiger's  Arch.,  xlvii.,  p.  601. 

Rothschild.     Beitr.  z.  klin.  Chir.,  xxxv.,  p.  281. 

XXV.     CHLORINE  AND  BROMINE. 

Chlorine  and  bromine  resemble  each  other  closely  in  the  effect 
which  they  induce  in  all  forms  of  living  matter.  These  may  be  ex 
plained  in  part  by  their  replacing  hydrogen  in  its  combinations  in  th 
proteids  and  forming  hydrochloric  or  hydrobromic  acid  with  the  hydro 
gen  set  free,  in  part  by  their  combining  with  the  hydrogen  of  wate 
and  thus  liberating  nascent  oxygen,  which  then  acts  on  the  tissues 
The  latter  process  is  believed  to  account  for  the  fact  that  chlorine  is 
much  more  powerful  disinfectant  in  moist  air  than  in  dry.  In  th 
higher  organisms  all  of  these  reactions  probably  occur  together. 

Action.  —  Chlorine  and  bromine  are  general  protoplasm  poisons 
thus  3  parts  of  chlorine  in  1,000  parts  of  moist  air  are  sufficient  t 
destroy  the  spores  of  most  bacteria  in  the  course  of  three  hours,  an< 
the  infusoria  and  the  higher  plants  have  been  shown  to  be  equall; 
susceptible  to  the  influence  of  the  gas.  Even  smaller  quantities  01 
bromine  are  disinfectant. 

In  the  higher  animals  and  in  man  chlorine  and  bromine  act  a 
irritants.  Thus  chlorine  water  (a  saturated  solution  of  chlorine  ii 


CHLORINE  AND  BROMINE.  583 

Water)  induces  irritation  and  redness  of  the  skin,  and  even  blistering, 
when  the  gas  is  prevented  from  escaping,  Bromine  also  causes  very 
painful  blistering,  the  fumes  penetrating  more  deeply  into  the  tissues 
than  the  non-volatile  irritants,  and  causing  more  widespread  irritation. 
Bromine  or  chlorine  water,  when  swallowed,  elicits  intense  inflamma- 
tion and  corrosion  of  the  mouth,  throat  and  stomach,  with  collapse  and 
all  the  ordinary  effects  of  gastric  irritation.  Air  containing  even  a 
very  small  proportion  of  chlorine  irritates  the  eyes,  nose,  larynx  and 
the  deeper  respiratory  passages,  the  bronchi  and  lungs  seeming  more 
susceptible  than  the  rest  of  the  tract,  for  bronchitis,  pulmonary  con- 
gestion and  haemorrhages,  coughing  and  pain  in  the  thorax  are  induced 
by  quantities  that  cause  little  or  no  irritation  of  the  mouth  and  nose. 
Lehmann  found  that  one  volume  of  chlorine  or  bromine  vapor  in  one 
million  parts  of  air  cause  some  irritation,  but  no  serious  results,  but 
that  ten  volumes  in  the  same  amount  of  air  inhaled  for  some  time, 
cause  haemorrhage  and  inflammation  of  the  lungs,  severe  bronchitis  and 
other  similar  effects.  After  fatal  poisoning  from  the  inhalation  of 
bromine,  he  observed  marked  irritation  of  the  gastric  mucous  mem- 
brane, while  this  symptom  was  absent  after  chlorine.  Another  point 
in  which  bromine  differs  from  chlorine  is  in  its  powerful  action  on  the 
hair,  which  is  rendered  soft  and  gelatinous,  and  eventually  removed 
entirely  by  exposure  for  some  time  to  the  vapor. 

These  symptoms  of  chlorine  and  bromine  poisoning  are  caused  by  their 
local  action  only,  and  are  so  severe  that  they  might  conceal  those  induced 
by  the  effects  of  the  halogens  after  absorption.  The  greater  proportion  of 
the  poisons  is  undoubtedly  changed  to  hydrochloric  and  hydrobromic  acids, 
and  these  again  to  chlorides  and  bromides  in  the  course  of  absorption.  But 
it  seems  possible  that  some  may  form  proteid  compounds  in  the  body  (as 
happens  in  ths  test-tube),  and  that  these  may  have  some  action.  As  a  mat- 
ter of  fact  both  chlorine  and  bromine  are  stated  to  have  a  narcotic  effect  on 
the  brain  quite  apart  from  their  local  effects,  but  nothing  further  is  known 
of  their  action  in  the  tissues.  Attention  has  been  drawn  to  a  number  of  cases 
in  which  symptoms  arose  in  workmen  in  chemical  factories  where  chlorine  is  lib- 
erated by  electrolysis,  or  more  rarely  in  others  where  hydrochloric  acid  is  formed 
in  large  quantities.  The  most  marked  symptom  is  an  affection  of  the  sebaceous 
glands,  from  which  the  condition  receives  its  name  of  chlorine  acne,  but  this 
often  induces  headache,  sleeplessness,  loss  of  appetite,  and  ansemia.  No  satis- 
factory explanation  of  the  symptoms  has  been  given,  nor  is  it  known  whether 
the  chlorine  or  some  unknown  body  is  the  cause  (Lehmann,  Jacquet). 

PREPARATIONS. 

Liquor  Chlori  Compositus  (U.  S.  P.),  chlorine  water,  contains  at  least  4  parts 
of  the  gas  in  1,000  parts  of  water.  It  is  a  clear,  greenish  liquid  with  the  suf- 
focating odor  of  chlorine  and  is  liable  to  form  hydrochloric  acid,  especially  when 
exposed  to  the  air  and  sunlight.  It  ought  therefore  to  be  freshly  prepared  when 
the  full  strength  is  required. 

Calx  Chlorinata  (U.  S.  P.,  B.  P.),  chlorinated  lime,  bleaching  powder,  some- 
times erroneously  called  chloride  of  lime,  is  a  compound  formed  by  the  action  of 
chlorine  on  lime.  It  consists  of  a  mixture  of  calcium  hypochlorite  (Ca(ClO)a), 
calcium  chloride  (CaCl2),  lime  and  water.  The  hypochlorite  is  very  unstable 
and  gives  off  chlorine  in  air,  and  especially  in  the  presence  of  an  acid.  Strong 
acids  also  free  the  hydrochloric  acid  of  the  chloride,  and  this  is  decomposed  by 
the  hypochlorite  into  chlorine  and  water.  Chlorinated  lime  forms  a  white  or 


584  INORGANIC  SALTS,  ACIDS  AND  EASES. 

grayish- white  powder,  with  the  odor  of  chlorine.  It  is  only  partially  soluble  in 
water  and  must  contain  not  less  than  35  per  cent,  of  available  chlorine,  U.  S.  P.  ; 
33  per  cent.  B.  P. 

Liquor  Calcis  Chlorinates  (B.  P.). — The  solution  should  yield  about  3  per  cent, 
of  chlorine. 

Liquor  Sodce  Chlorinatce  (U.  S.  P.,  B.  P.),  sorution  of  chlorinated  soda,  Labar- 
raque's  solution  or  Javelle's  solution,  is  formed  from  chlorinated  lime  and  con- 
tains hypochlorite  of  soda  (NaCIO)  and  chloride  of  soda.  Like  the  correspond- 
ing lime  salt,  it  has  the  odor  of  chlorine  and  bleaches  vegetable  colors.  It  must 
contain  at  least  2. 6  per  cent,  by  weight  of  available  chlorine,  U.  S.  P.  ;  2. 5  per 
cent.,  B.  P.  10-20  mins. 

Bromum  (U.  S.  P.),  bromine,  '*  heavy,  brownish-red  liquid  evolving  a  yel- 
low-red, very  irritant  vapor. 

Chlorine  was  formerly  used  internally  in  infectious  disease,  but  this 
has  been  entirely  abandoned,  since  it  has  been  recognized  that  it  is 
much  more  poisonous  to  the  higher  animals  than  to  the  micro-organ- 
isms. The  inhalation  of  chlorine  in  phthisis  has  also  fallen  into  dis- 
use for  the  same  reason.  Chlorine  water  and  the  solution  of  chlori- 
nated soda  are  still  occasionally  used  as  antiseptic,  deodorant  solutions 
in  the  treatment  of  foul  sores,  and,  more  rarely,  to  disinfect  the  hands 
before  operation  ;  both  preparations  are  very  irritant,  however.  Chlo- 
rine water  much  diluted  has  been  used  as  a  gargle,  as  a  vaginal  injec- 
tion and  for  other  similar  purposes. 

The  chlorine  preparations  are  chiefly  used  to  disinfect  fseces,  urinals 
and  to  a  less  extent  rooms  and  houses  ;  for  this  purpose  chlorinated 
lime  is  the  most  suitable,  especially  wheu  acid  is  added  to  it  in  excess. 
The  room  ought  to  be  hermetically  sealed,  and  the  fumes  are  of  no 
value  as  disinfectants  unless  they  are  present  in  such  quantity  as  to 
render  the  air  quite  irrespirable.  They  have  the  disadvantage  that 
they  bleach  most  of  the  colors  used  in  dyeing,  and  fail  to  penetrate  in 
sufficient  quantity  into  the  clothing,  which  they  also  corrode  to  some 
extent.  Chlorinated  lime  exposed  in  the  sick-room  merely  serves  as 
a  deodorant,  and  has  no  disinfectant  value,  but  has  the  disadvantage 
of  giving  a  false  feeling  of  security  like  other  similar  measures. 
Chlorine  seems  inferior  to  sulphurous  acid  anhydride,  and  still  more 
so  to  formalin  as  a  disinfectant,  not  from  its  being  weaker  in  action, 
but  because  it  is  more  difficult  to  apply  in  sufficient  quantity.  Chlo- 
rinated lime  can,  however,  be  applied  in  urinals  and  closets,  where 
both  these  disinfectants  are  unavailable.  Here  it  acts  again  as  a  de- 
odorant, while  its  disinfectant  value  is  smaller. 

Bromine  is  also  powerfully  disinfectant,  but  has  not  been  used  prac- 
tically for  this  purpose  in  recent  years.  It  is  occasionally  employed 
as  a  corrosive,  e.  g.,  in  disease  of  the  os  uteri. 

In  Poisoning  with  chlorine  taken  by  the  mouth,  alkalies  are  advised 
with  the  view  of  neutralizing  the  acid  formed,  and  narcotics  may  be 
necessary  for  the  pain.  In  cases  of  poisoning  by  inhalation,  steam 
may  be  inhaled  to  lessen  the  irritation,  and  ammonia  has  been  advised, 
but  is  itself  irritant.  In  corrosion  of  the  skin  with  bromine,  one  half 
per  cent,  carbolic  acid  has  been  applied  with  success,  it  is  said,  the 


OXYGEN.  585 

bromine  being  precipitated  as  bromphenol.     Vapor  of  carbolic  acid 
has  also  been  inhaled  in  bromine  irritation  of  the  nose  and  throat. 


BIBLIOGRAPHY. 

Binz,     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxiv.,  p.  194. 
Lehmann.     Arch.  f.  Hygiene,  vii.,  p.  231  ;  xxxiv.,  p.  308. 
Fischer  u.  Proskauer.     Mittheil.  a.  d.  Gesundheitsamt,  ii.,  p.  228. 
Cash.     Keports  of  Brit.  Local  Gov.  Board,  1886. 
Lehmann.     Arch.  f.  Hygiene,  xlvi.,  p.  322. 


Jacquet.     Semaine  medicale,  Dec.  31,  1902. 

XXVI.     OXYGEN. 

Ever  since  the  discovery  of  the  relation  of  oxygen  to  the  respiration,  at- 
tempts have  been  made  to  use  it  in  therapeutics,  by  inhaling  the  gas  pure  or 
mixed  with  air,  or  by  spending  a  certain  time  each  day  in  chambers  of  com- 
pressed air.  It  was  expected  that  by  these  means  a  larger  amount  of  oxygen 
would  be  absorbed,  and  a  more  active  combustion  in  the  tissues  would  be 
induced.  The  absorption  of  oxygen  by  the  lungs  does  not  depend  on  the 
partial  pressure  of  the  oxygen,  however,  but  on  its  affinity  for  the  reduced 
haemoglobin  of  the  corpuscles.  It  is  true  that  the  oxygen  dissolved  in  the 
plasma  is  increased  by  a  great  rise  in  the  barometric  pressure,  or  by 
inhaling  pure  oxygen,  but  this  dissolved  oxygen  is  trifling  in  amount  com- 
pared with  that  in  combination  with  the  haemoglobin.  Under  ordinary  con- 
ditions, then,  the  air  is  sufficient  to  oxidize  almost  all  the  reduced  haemo- 
globin passing  through  the  lungs,  and  oxygen  lessens  but  slightly  the  small 
proportion  that  escapes  by  the  pulmonary  veins  unoxidized.  As  far  as  the 
tissues  are  concerned,  the  oxidation  is  of  course  the  same  whether  the  oxy- 
hsemoglobin  carried  to  them  by  the  blood  was  formed  in  a  pure  atmosphere 
of  oxygen  or  in  air,  of  which  it  comprises  only  about  20  per  cent.  The 
slight  increase  in  the  oxyhaemoglobin  of  the  blood  has  no  appreciable  effect, 
as  more  oxygen  is  offered  to  the  tissues  normally  than  they  can  assimilate. 
It  is  therefore  inconceivable  that  the  very  slight  increase  in  the  quantity  of 
oxygen  in  the  blood  can  have  any  effect  on  the  oxidation  in  the  tissues  under 
ordinary  conditions.  But  if  the  gas  be  inhaled  under  high  pressure  the  aug- 
mented tension  in  the  blood  may  induce  some  symptoms,  and  this  is,  according 
to  Smith,  the  explanation  of  a  tendency  to  tetanic  convulsions  which  he  found 
developed  in  animals  under  these  circumstances  ;  hilarity  and  some  other  nerv- 
ous effects  are  said  to  have  been  induced  in  man  in  some  instances,  and  these 
may  also  be  interpreted  as  the  results  of  the  high  oxygen  tension  in  the  blood, 
if  they  were  not  the  products  of  fancy  and  suggestion.  Oxygen  inhalation  is 
therefore  incapable  of  increasing  the  oxidation  in  the  tissues,  or  in  fact  of  modi- 
fying in  any  way  the  metabolism,  and  experience  has  shown  it  to  be  valueless  in 
such  constitutional  diseases  as  diabetes  and  gout,  in  which,  moreover,  it  has  been 
demonstrated  that  there  is  no  deficiency  in  the  oxygen  of  the  blood. 

The  further  question  arises  whether  oxygen  inhalation  is  likely  to  be  of 
benefit  in  the  cyanosis  due  to  severe  cardiac  or  pulmonary  disease.  Improve- 
ment is  very  often  observed  clinically,  the  skin  losing  its  dark  color,  and  the 
respiration  and  heart  becoming  less  rapid  and  labored  as  soon  as  the  inhala- 
tion is  commenced,  and  alarming  symptoms  returning  when  it  is  stopped. 
This  may  be  explained  by  the  larger  amount  of  oxygen  dissolved  in  the 
plasma  ;  when  air  is  breathed,  the  plasma  contains  only  about  0.6  per  cent, 
of  oxygen  in  simple  solution,  but  when  oxygen  is  inhaled  the  percentage 
may  rise  to  3  per  cent,  and  this  may  reinforce  the  oxygen  carried  by  the 
haemoglobin.  In  cases  in  which  only  a  small  quantity  of  blood  is  passed 
through  the  lungs  owing  to  circulatory  disorder  or  where  the  aerating  surface 


586  INORGANIC  SALTS,  ACIDS  AND  BASES. 

of  the  lungs  is  diminished  by  exudation,  this  small  supplementary  supply  of 
oxygen  may  be  of  importance.  Again  the  air  actually  inspired  does  not  pass 
directly  into  the  alveoli,  but  diffuses  from  the  wider  air  passages  into  the 
narrower  ones  and  then  reaches  the  absorbent  surfaces.  Pure  oxygen  diffuses 
more  rapidly  and  in  larger  quantity  into  the  alveoli  than  when  it  is  mixed 
with  nitrogen,  and  it  is  therefore  conceivable  that  when  the  movement  of 
the  air  in  the  air  passages  is  insufficient,  oxygen  may  give  relief  by  diffusing 
in  larger  quantity  into  the  alveoli.  Insufficient  movement  of  the  air  currents 
may  be  due  to  obstruction  of  the  respiratory  tract,  as  in  asthma  or  severe 
bronchitis,  or  to  slow  and  shallow  breathing  from  depression  of  the  centre. 
Accordingly,  the  inhalation  of  oxygen  is  said  to  be  followed  by  relief  in 
some  cases  of  asthma  and  bronchitis,  and  it  has  been  recommended  in  nar- 
cotic poisoning. 

When  the  haemoglobin  of  the  blood  is  so  altered  as  to  be  incapable  of 
transporting  oxygen  to  the  tissues,  as  in  cases  of  poisoning  with  carbon  mon- 
oxide, nitrites,  chlorates,  nitrobenzol,  etc.,  oxygen  inhalation  is  indicated,  for 
it  has  been  shown  by  Haldane  and  others  that  the  plasma  dissolves  enough 
oxygen  to  maintain  life  when  that  supplied  by  the  blood  corpuscles  is  insuf- 
ficient. The  inhalation  has  to  be  continued  until  the  symptoms  of  deficient 
aeration  have  disappeared. 

Many  microbes  are  killed  or  at  any  rate  much  retarded  in  their  growth 
when  freely  exposed  to  the  air,  and  attempts  have  been  made  to  treat  pul- 
monary phthisis  by  oxygen  inhalation.  The  results  have  been  less  disas- 
trous than  those  of  some  of  the  other  treatments  by  inhalation,  but  no  dis- 
tinct benefit  has  accrued,  and  in  some  cases  haemoptysis  has  been  induced 
by  it  from  some  unexplained  cause.  Smith  has  recently  found  that  the  in- 
halation of  oxygen  under  some  pressure  causes  irritation,  congestion  and 
consolidation  of  the  lungs  in  mice  and  birds. 

Oxygen  is  inhaled  through  a  mask  connected  with  a  large  container  which 
is  filled  from  a  tank  of  the  compressed  gas.  Very  often  the  oxygen  may  be 
diluted  with  air  and  for  this  purpose  a  small  opening  may  be  made  in  the 
mask. 

Ozone,  or  active  oxygen  (O3),  is  a  much  more  powerful  oxidizing  body  than 
ordinary  oxygen,  but  is  more  easily  reduced  than  peroxide  of  hydrogen. 
It  has  a  curious  phosphorous  odor  and  is  somewhat  irritant  to  the  respiratory 
membranes,  but  it  is  almost  always  accompanied  by  nitrogen  oxides,  and 
some  of  the  properties  which  have  been  ascribed  to  ozone  may  be  due  to 
these  impurities.  It  is  rapidly  decomposed  by  living  matter,  and  it  seems 
very  improbable  that  it  can  be  absorbed  into  the  blood  ;  yet  Binz  and 
Schulz  believe  that  ozone  induces  narcosis  in  dogs,  rabbits  and  kittens,  and 
Schulz  found  in  experiments  in  which  ozone  was  inhaled  repeatedly  for  long 
periods  that  it  induced  vomiting  and  dyspnoea,  bronchitis,  oedema  and  blood- 
extravasation  in  the  lungs  ;  conjunctivitis  also  occurred  in  some  experiments. 
Schulz  ascribes  these  symptoms  to  the  ozone,  but  they  may  be  due  in  part  at 
any  rate  to  the  impurities,  or  perhaps  to  oxygen. 

Ozone  has  undoubtedly  antiseptic  properties,  but  these  are  only  apparent 
when  air  contains  13.5  mg.  or  more  per  litre.  Even  this  disinfects  only  the  air 
itself  and  the  surfaces  of  objects,  as  the  ozone  loses  its  oxidizing  properties  when- 
ever it  comes  in  contact  with  organic  matter  and  therefore  fails  to  penetrate.  It 
has  recently  been  advocated  to  disinfect  drinking  water. 

Ozone  inhalation  has  been  recommended  in  the  hope  of  increasing  the 
oxidation  of  the  tissues,  and  as  an  antiseptic  in  pulmonary  phthisis,  but  its 
irritant  properties  preclude  its  use  here,  and  it  has  been  generally  discarded. 
It  was  supposed  to  be  formed  in  turpentine  oil  on  standing,  and  old  turpen- 
tine oil  was  therefore  recommended  in  cases  of  phosphorus  poisoning, 
with  the  hope  that  it  would  tend  to  oxidize  the  phosphorus  and  render  it 
harmless.  Recent  investigations  show,  however,  that  no  ozone  is  formed  in 
turpentine  oil,  and  there  is  no  reason  to  suppose  that  the  treatment  is  of 
benefit. 


PEROXIDE  OF  HYDROGEN.  587 

Antozon  is  a  mixture  of  oxygen  and  peroxide  of  hydrogen,  and  many  other 
so-called  solutions  of  ozone  contain  only  small  percentages  of  the  peroxide 
and  no  ozone  proper,  as,  though  the  latter  is  soluble  in  water,  it  decomposes 
very  rapidly,  only  traces  of  it  being  found  in  the  solution  after  10-15  days. 
It  breaks  up  into  oxygen,  and  does  not  form  hydrogen  peroxide. 

The  ozone  of  the  air  has  been  appealed  to,  in  order  to  explain  and  adver- 
tise the  benefits  induced  by  many  watering  places  and  forest  resorts  but  it 
has  never  been  satisfactorily  proved  that  the  air  in  these  localities  contains 
more  ozone  than  in  other  less  favored  places.  The  curative  agency  is  gen- 
erally the  change  of  scene  and  interests,  and  the  dietary. 

BIBLIOGRAPHY. 

Smith.     Jour.  ofPhysiol.,  xxii.,  p.  307;  xxiv.,  p.  19. 

Haldane,  Makgill  and  Mavrogordato.     Jour.  ofPhysiol.,  xxi.,  p.  160. 

Michaelis.     Verhandl  d.  Congresses  f.  inn.  Med.,  1900,  p.  503. 

Binz.     Berl.  klin.  Woch.,  1882  and  1884. 

Sonntag.     Ztschr.  f.  Hygiene,  viii.,  p.  95. 

Cash.     Keports  of  Brit.  Local  Gov.  Board,  1885. 

Schulz.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix.,  p.  364. 

Hasenfcnopf.     Charite-annalen,  xxviii.,  p.  228. 

Durig.     Arch.  f.  Anat.  u.  Phys.,  1903,  Supplem.,  p.  209. 

Cowl  and  Royovin.     Ibid.,  1904,  p.  1. 

Hill  and  Madeod.     Proc.  Roy.  Soc.,  Ixx.,  p.  455. 

Bohr  and  Maar.     Skand.  Arch.  f.  Phys.,  xvi.,  p.  41. 

XXVII.     PEROXIDE  OF  HYDROGEN. 

Hydrogen  peroxide  or  dioxide  (H2O2)  tends  to  break  down  into 
water  and  oxygen  very  rapidly  in  the  presence  of  many  substances, 
which  in  themselves  may  be  either  oxidizing  or  reducing.  Among  the 
bodies  which  induce  this  decomposition  or  catalysis  are  all  forms  of 
living  matter,  and  the  peroxide  of  hydrogen  is  therefore  decomposed 
when  brought  in  contact  with  the  tissues,  the  oxygen  thus  liberated 
in  a  nascent  condition  tending  to  oxidize  its  surroundings  ;  the  chief 
effects  of  this  liquid  are  therefore  due  to  its  oxidizing  properties.  It  is 
generally  met  with  in  dilute  solution  in  water,  and  in  this  form  alone 
is  used  in  medicine.  Brought  in  contact  with  the  skin,  peroxide  of 
hydrogen  solution  is  decomposed,  and  numerous  bubbles  of  oxygen  are 
formed,1  but  this  decomposition  proceeds  much  more  rapidly  when  it  is 
applied  to  denuded  surfaces  or  to  mucous  membranes.  The  oxygen  is 
formed  in  such  quantity  that  some  irritation  may  follow,  and  thus 
dogs  often  vomit  when  it  is  administered  in  quantity  by  the  mouth. 
When  it  is  injected  subcutaneously,  a  large  amount  of  oxygen  is 
formed  in  the  subcutaneous  tissues,  but  some  of  the  peroxide  escapes 
decomposition  and  is  absorbed  into  the  blood.  Here  the  decomposi- 
tion proceeds  more  violently,  the  red  blood  cells  having  a  strong  cata- 
lytic action,  and  the  oxygen  set  free  may  cause  emboli  and  lead  to 
sudden  death.  The  formation  of  emboli  is  seen  most  frequently  in 
the  rabbit,  but  was  in  all  probability  the  cause  of  death  in  one  case  of 
fatal  poisoning  in  man,  in  which  a  solution  of  hydrogen  peroxide  had 
been  used  to  wash  out  the  pleural  cavity.2  Emboli  are  not  formed  in 

1 A  concentrated  solution  is  said  to  corrode  the  skin,  leaving  a  white  eschar. 
2  In  several  other  instances  hemiplegia  has  been  observed,  apparently  from  embolism 
of  the  cerebral  arteries. 


588  INORGANIC  SALTS,  ACIDS  AND  BASES. 

the  dog  on  hypodermic  injection,  nor  in  either  dogs  or  rabbits  poisoned 
by  the  stomach — in  the  latter  case  probably  because  the  liquid  is  more 
slowly  absorbed  and  is  almost  entirely  decomposed  in  the  mucous 
membrane.  Even  in  the  blood  and  tissues  the  whole  of  the  peroxide 
is  not  decomposed,  for  several  observers  have  found  traces  of  it  ex- 
creted in  the  urine. 

Injected  intravenously  in  either  dogs  or  rabbits  the  peroxide  is  rap- 
idly decomposed  in  the  blood,  and  forms  emboli  which  prove  immedi- 
ately fatal  by  stopping  the  circulation  through  the  lungs,  heart  and 
brain. 

The  action  of  hydrogen  peroxide,  then,  apart  from  its  local  effects  is  ex- 
plained by  its  obstructing  the  blood  vessels  mechanically.  Colasanti  has 
stated  recently  that  in  addition  it  forms  methsemoglobin  in  dogs  and  thus 
leads  to  a  marked  decrease  in  the  metabolism  from  the  non-aeration  of  the 
tissues,  but  his  statement  requires  further  confirmation. 

The  catalytic  decomposition  of  the  peroxide  is  not  necessarily  asso- 
ciated with  the  life  of  the  tissues,  for  it  occurs  also  in  excised  organs 
and  in  drawn  blood.  In  fact,  it  was  formerly  supposed  that  it  took 
place  only  in  the  blood  outside  the  tissues,  and  that  the  circulating 
blood  had  no  effect  on  it,  but  this  has  been  shown  to  be  erroneous. 
The  different  organs  vary  considerably  in  their  catalytic  power,  the 
red  blood  cells  and  the  liver  cells  being  the  most  active,  and  it  has 
been  stated  that  this  action  of  the  tissue  cells  is  closely  associated  with 
the  presence  of  nucleoproteids  (Gottstein,  Spitzer) ;  but  Loew  has 
shown  that  it  is  due  to  the  presence  of  a  widely  distributed  ferment 
(catalase)  in  most  instances. 

The  catalysis  of  hydrogen  peroxide  occurs  in  the  lower  forms  of  life 
as  well  as  in  the  higher.  Thus  germinating  seeds,  yeasts,  infusoria 
and  the  microbes  all  free  oxygen  from  the  solution,  and  in  fact,  a 
rough  estimate  of  the  number  of  microbes  in  water  may  be  formed 
from  the  amount  of  oxygen  given  off  by  it  on  the  addition  of  the  per- 
oxide (Gottstein)o  This  decomposition  is  fatal  to  most  of  these  lower 
forms,  presumably  from  the  nascent  oxygen,  and  peroxide  of  hydrogen 
is  therefore  a  powerful  disinfectant,  a  three  per  cent,  solution  proving 
as  strongly  bactericidal  as  a  one  per  mille  solution  of  corrosive  subli- 
mate ;  but  when  the  microbes  are  contained  in  a  medium  with  much 
organic  substance,  as  in  wounds,  the  bactericidal  action  is  very  much 
reduced. 

In  recent  years,  attention  has  been  drawn  to  other  bodies  analogous 
to  hydrogen  peroxide,  some  of  which  possess  powerful  microbicidal 
properties.  The  peroxide  is  represented  by  the  structural  formula 
H — O — O — H  and  one  of  the  hydrogens  may  be  replaced  by  benzoyl 
or  acetyl,  forming  C6H5CO— O— OH  (benzo-peracid)  or  CH3CO 
— OOH  (aceto-peracid).  These  have  been  shown  to  be  much  more 
powerful  germicides  than  hydrogen  peroxide,  while  they  give  off 
oxygen  less  readily  ;  in  fact  they  are  comparable  only  to  corrosive 
sublimate  in  their  destructive  effect  on  microorganisms  and  even  sur- 


PEROXIDE  OF  HYDROGEN.  589 

pass  it  in  favorable  conditions.  This  suggests  that  the  disinfectant 
action  of  this  group  is  not  really  due  to  its  liberating  oxygen  only, 
otherwise  the  activity  of  these  peracids  would  be  less  than  that  of  the 
peroxide  as  they  part  with  their  oxygen  less  readily.  It  is  possible, 
however,  that  the  difference  really  arises  from  the  way  in  which  the 
oxygen  is  liberated ;  for  example,  the  peracids  may  penetrate  the 
microbes  and  free  oxygen  in  their  interior,  while  the  peroxide  is  re- 
duced before  it  passes  through  the  cell-wall.  The  peracids  are  pre- 
pared with  difficulty  and  are  very  unstable  bodies,  so  that  it  is  unlikely 
that  they  will  prove  of  value  in  practical  medicine.  But  they  are 
formed  when  the  aqueous  solutions  of  some  more  readily  available 
substances  are  allowed  to  stand  for  some  time.  In  these  both  the  hy- 
drogen atoms  of  hydrogen  peroxide  are  replaced  by  organic  radicles 
forming  organic  peroxides  such  as  diacetyl  peroxide  (CH3CO — O — O 
— COCH3)  and  benzoyl-acetyl-peroxide  (C6H5CO— O— 6— COCH3), 
On  dissolving  these  in  water,  the  peracids  are  formed  and  the  solutions 
are  very  powerful  disinfectants  which  have  been  suggested  for  surgical 
use  and  also  as  intestinal  disinfectants ;  practical  clinical  experience 
alone  can  decide  whether  they  possess  that  value  which  the  results  in 
the  laboratory  seem  to  indicate. 

PREPARATION. 

Aqua  Hydrogenii  Dioxidi  (U.  S.  P.),  Liquor  Hydrogenii  Peroxidi  (B.  P.), 
solution  of  hydrogen  dioxide  or  peroxide,  contains  about  3  per  cent,  by 
weight  of  the  pure  dioxide.  Each  volume  of  this  solution  is  capable  of  set- 
ting free  9-11  volumes  of  oxygen  when  completely  decomposed.  Some  acid 
is  added  to  the  peroxide  solution  in  order  to  retard  its  decomposition,  but  it 
gradually  changes  when  kept,  so  that  only  freshly  prepared  solutions  are  of 
full  strength.  The  solution  is  colorless  and  odorless,  but  has  an  acid  taste 
from  the  added  acid,  and  the  oxygen  freed  in  the  mouth  gives  a  curious  sen- 
sation and  forms  a  froth. 

Therapeutic  Uses.  —  Hydrogen  dioxide  is  used  locally  as  a  disinfect- 
ant solution  in  suppuration,  diphtheria  and  urethral  infection.  In  pus 
cavities  the  oxygen  is  freed  with  great  rapidity,  and  the  pus-corpuscles 
are  said  to  be  disintegrated.  The  catalysis  is  due  in  part  to  these  cor- 
puscles, in  part  to  the  microbes,  and  the  extent  of  the  suppuration 
may  be  estimated  from  the  amount  of  effervescence.  Peroxide  solu- 
tions differ  from  most  other  disinfectants  in  the  short  duration  of  the 
action,  which  passes  off  as  soon  as  all  the  oxygen  is  liberated.  In  ad- 
dition to  its  microbicidal  action  proper,  this  agent  loosens  and  destroys 
masses  of  infected  material  by  the  mechanical  effect  of  the  liberation 
of  the  gas,  and  the  wound  or  cavity  is  thus  cleaned  by  it  more  per- 
fectly than  by  washing  with  ordinary  antiseptic  solutions.  The  solu- 
tion has  been  recommended  for  use  in  ophthalmic  practice,  and  for 
this  purpose  may  be  diluted  one  half. 

BIBLIOGRAPHY. 

Gutimann.     Virchow's  Arch.,  Ixxiii.,  p.  23  ;  Ixxv.,  p.  255. 

Schwerin.     Ibid.,  Ixxiii.,  p.  37. 

Altehoefer.     Centralbl.  f.  Bacteriol.,  viii.,  1890,  p.  129. 


590  INORGANIC  SALTS,  ACIDS  AND  BASES. 

Pane.     London  Medical  Kecord,  1891. 

Colasanti  and  Brugnola.     Arch.  Ital.  de  Biol.,  xxv.,  p.  228. 

Goltstein.     Virchow's  Arch.,  cxxxiii.,  p.  295. 

Spitzer.     Pfliiger's  Arch.,  Ixvii.,  p.  615. 

Honsell.     Beitrage  z.  klein.  Chir.,  xxvii.,  p.  127. 

Losw.     U.  S.  Depart,  of  Agriculture  Rep.,  No.  68. 

Novy  and  Freer.     Journ.  of  Exp.  Med.,  vi.     (Peracids. ) 

Other  Oxidizing  Disinfectants. 

Other  oxidizing  bodies  have  been  used  as  antiseptics  and  disinfect- 
ants. Thus  Calcium  Peroxide  or  Gorit  has  been  recommended  as  a 
gastric  and  intestinal  disinfectant  for  children  in  doses  of  0.2-0.6  G. 
in  milk.  Zinc  peroxide  and  magnesium  peroxide  have  also  been  sug- 
gested, the  former  for  external,  the  latter  for  internal  use. 

Similarly  the  Persulphates  of  potassium  and  sodium  (Na2S2O8),  per- 
sodine,  possess  strong  oxidizing  properties  from  their  liberating  oxygen 
in  contact  with  organic  matter.  They  are  only  feebly  poisonous  but 
have  not  been  extensively  used  as  yet. 

Some  older  and  better  known  disinfectants  also  owe  their  powers  to 
liberated  oxygen,  and  among  these  that  most  largely  employed  is  the 
Permanganate  of  Potassium. 

When  a  solution  of  this  salt  comes  in  contact  with  organic  matter, 
such  as  albumin,  the  permanganate  at  once  parts  with  some  of  its 
oxygen,  which  attaches  itself  to  the  albumin.  Permanganate  is  thus 
poisonous  to  protoplasm,  not  through  the  presence  of  the  whole  mole- 
cule, but  in  consequence  of  the  oxidation  of  the  proteids.  As  soon  as 
the  permanganate  is  reduced,  it  of  course  loses  this  action,  so  that  the 
oxidizing  effect  is  limited  to  the  skin  and  the  surface  of  the  mucous 
membranes.  Concentrated  solutions  irritate,  and  even  corrode  the  skin, 
and  induce  gastro-enteritis  when  swallowed.  Permanganate  solutions 
are  disinfectants  of  considerable  power,  owing  to  their  oxidizing  and 
thus  destroying  bacteria.  They  fail  to  penetrate  deeply  in  an  active 
form,  and  this  renders  them  of  less  value  than  many  other  disinfect- 
ants, except  in  very  superficial  infection. 

PREPARATIONS. 

Potassii  Permanganas  (U.  S.  P.,  B.  P.)  (KMnO4)  forms  slender  crystals  of 
a  dark  purple  color  and  a  sweetish,  afterwards  disagreeable  and  astringent 
taste,  soluble  in  sixteen  parts  of  water,  reduced  by  alcohol  and  other  or- 
ganic bodies.  0.05-0.2  G.  (1-3  grs.),  in  pills  made  up  with  kaolin. 

Liquor  Potassii  Permanganatis  (B.  P.),  a  1  per  cent,  solution  in  water. 
2-4  fl.  drs. 

Therapeutic  Uses.  —  The  permanganate  has  been  used  internally  in 
amenorrhcea  and  chlorosis. 

Externally  it  is  used  for  its  disinfectant  and  deodorant  action,  as  an 
application  to  gangrenous  ulcers,  cancerous  sores,  diphtheria,  and  gon- 
orrhoea. In  dilute  solution  it  may  be  used  as  a  gargle  and  mouth 
wash  (1  per  cent.),  to  disinfect  the  hands  (1-3  per  cent.),  which  it  stains 
brown,  and  for  other  similar  purposes. 

It  has  recently  been  recommended  in  poisoning  with  phosphorus, 
prussic  acid,  morphine  and  other  alkaloids,  on  the  theory  that  these 


PHOSPHORUS.  591 

poisons  are  oxidized  by  it  in  the  stomach,  and  thus  rendered  harm- 
less. For  this  purpose  it  is  given  in  J  per  cent,  solution.  It  may  be 
questioned  whether  much  permanganate  reaches  the  stomach  unreduced, 
and  the  method  is  certainly  less  reliable  than  the  stomach  tube.  Only 
the  poison  actually  in  the  stomach  is  destroyed,  permanganate  having, 
of  course,  no  effect  upon  that  absorbed  into  the  blood.  In  snakebite, 
permanganate  has  been  advised,  and  it  undoubtedly  has  some  action  on 
the  poison  when  it  comes  in  contact  with  it,  and  may  therefore  be 
used  to  wash  the  wound  and  also  to  inject  around  it ;  it  has  no  effect 
upon  the  poison  already  absorbed. 

Condy's  Fluid  is  a  strong  solution  of  impure  permanganate,  which 
is  of  use  to  disinfect  and  deodorize  urinals  and  faeces,  but  must  be 
poured  on  them,  and  cannot  be  employed  to  disinfect  rooms. 

Some  of  the  caustics  owe  part  of  their  action  to  the  oxygen  liber- 
ated when  they  come  in  contact  with  organic  matter.  Thus  Chromic 
Acid  destroys  tissue  in  part  through  its  acidity  but  this  is  reinforced 
by  its  oxidizing  powers. 

XXVIII.    PHOSPHORUS. 

In  the  early  part  of  last  century  phosphorus  played  a  very  important 
role  in  therapeutics,  and,  in  fact,  was  regarded  almost  as  a  panacea, 
but  at  present  its  use  is  much  more  restricted,  and  some  doubt  is  en- 
tertained as  to  its  possessing  any  therapeutic  value  whatever.  At 
the  same  time  it  has  been  the  subject  of  much  and  laborious  investiga- 
tion, partly  because  it  has  frequently  given  rise  to  poisoning,  and  partly 
because  the  study  of  its  effects  has  thrown  much  light  on  some  physi- 
ological and  pathological  processes.  It  differs  from  most  poisons  in 
acting  for  the  most  part  on  certain  phases  of  the  animal  metabolism, 
and  in  having  comparatively  little  direct  action  at  the  point  of  appli- 
cation, or,  indeed,  upon  any  single  organ. 

Phosphorus  is  absorbed  with  difficulty,  because  it  is  very  insoluble 
in  water  and  the  body  fluids  and  is  only  slowly  volatilized  at  ordinary 
body  temperature.  Large  masses  of  phosphorus  may  thus  pass  through 
the  alimentary  canal  without  serious  effects,  because  they  fail  to  be 
dissolved  and  absorbed.  But  when  it  is  taken  in  a  finely  divided  con- 
dition or  in  solution  in  oil,  it  gives  rise  to  symptoms  in  very  small 
quantity,  and  has  been  found  to  induce  fatal  poisoning  in  man  in  doses 
of  0.05-0.1  G.  (1-2  grs.).1  In  these  conditions  it  is  absorbed  partly  as 
vapor,  partly  in  solution  in  water,  which  dissolves  only  traces  how- 
ever, and  probably  chiefly  in  solution  in  the  fats  and  oils,  in  which  it 
is  much  more  soluble.  Phosphorus  vapor  is  also  absorbed  by  the  lungs, 
and  the  symptoms  of  chronic  poisoning  in  match  factories  are  believed 
to  arise  in  this  way.  It  does  not  seem  to  be  taken  up  from  the  skin, 
and  has  in  fact  little  effect  unless  when  rubbed  on  it,  when  it  ignites 
and  gives  rise  to  severe  burns ;  phosphorus  burns  do  not  cause 

1  Phosphorus  is  often  used  in  suicide,  generally  in  the  form  of  rat  poison  or  of  match 
heads.  Each  phosphorus  match  is  estimated  to  carry  3-5  mg.  of  phosphorus,  so  that 
15-20  match  heads  are  sufficient  to  induce  fatal  poisoning. 


592  INORGANIC  SALTS,   ACIDS  AND  BASES. 

phosphorus  poisoning,  however,  as  is  sometimes  stated.  The  red 
amorphous  phosphorus  is  much  less  poisonous  than  the  ordinary  yel- 
low form,  because  it  is  less  soluble  and  also  less  volatile,  and  conse- 
quently fails  to  be  absorbed. 

Phosphorus  exists  in  the  blood  as  such,  and  the  eifects  on  the  tissues 
are  unquestionably  due  to  the  element  itself,  and  not  to  the  oxygen  or 
hydrogen  compounds,  as  has  been  supposed.  Some  phosphuretted 
hydrogen  (PH3)  may  be  formed  in  the  bowel,  but  is  comparatively 
unimportant,  the  great  mass  of  the  phosphorus  being  absorbed  un- 
changed. As  soon  as  it  is  oxidized,  phosphorus  loses  its  specific  ac- 
tion, all  of  the  acids  being  comparatively  harmless.  Phosphorus  has 
been  detected  in  the  blood,  and,  it  is  said,  in  some  of  the  excretions. 

It  is  devoid  of  action  on  albumins  in  solution,  and  has  no  immediate 
irritant  eifects,  such  as  are  seen  in  poisoning  with  the  heavy  metals. 

Symptoms. — When  a  poisonous  dose  of  phosphorus  is  swallowed,  no 
effects  are  elicited  as  a  general  rule  for  several  hours.  The  first  symp- 
toms are  pain  and  discomfort  in  the  region  of  the  stomach,  nausea  and 
eructation  of  the  vapor  with  its  characteristic  garlic  odor,  and  then 
vomiting,  the  contents  of  the  stomach  having  the  same  odor,  and  being 
phosphorescent  in  the  dark.  Later,  bile  may  be  vomited,  and  some 
diarrhoea  may  set  in,  although  this  is  not  a  common  symptom.  The 
nausea  and  vomiting  often  continue  without  further  symptoms  for 
several  days,  but  frequently  disappear,  and  the  patient  apparently 
recovers,  particularly  if  the  dose  has  been  small,  or  if  most  of  it  has 
been  removed  by  vomiting  or  by  washing  out  the  stomach.  In  the 
course  of  a  few  days,  however,  the  symptoms  recur,  and  are  generally 
accompanied  by  some  jaundice ;  the  pain  extends  from  the  stomach  to 
the  liver,  and  soon  to  the  whole  of  the  abdomen.  The  vomited  matter 
no  longer  contains  phosphorus,  but  may  be  bloody.  The  patient  com- 
plains of  general  weakness  and  faintness  ;  the  pulse  is  weak,  the  liver  ex- 
tends far  below  the  ribs,  and  the  urine  shows  characteristic  changes  (see 
page  602);  haemorrhages  occur  from  the  nose,  bowel,  uterus,  and  under 
the  skin,  and  eventually  a  condition  of  collapse  and  fatal  coma  follow. 
Convulsions  and  delirium  have  been  observed  in  a  considerable  pro- 
portion of  cases  towards  the  termination  of  the  intoxication.  Death 
may  occur,  however,  in  the  first  stage  or  early  in  the  second,  before 
complete  exhaustion  is  reached,  and  in  these  cases  would  seem  to  be 
best  explained  by  the  direct  action  of  the  poison  on  the  heart.  If  only 
a  small  quantity  be  swallowed  or  if  active  therapeutic  measures  be 
taken  early,  the  patient  may  recover  without  any  secondary  symptoms, 
and  even  when  these  have  followed,  the  prognosis  is  not  hopeless,  for 
the  symptoms  slowly  disappear  in  a  certain  proportion  of  cases. 

Exposure  to  the  fumes  of  phosphorus  has  long  been  known  to  give 
rise  to  periostitis  and  necrosis  of  the  lower  jaw.  The  disease  begins 
from  a  carious  tooth  or  from  some  lesion  of  the  gum,  and  may  involve 
most  of  the  jaw,  which  becomes  swollen  and  painful  and  eventually 
evacuates  large  quantities  of  pus  with  pieces  of  dead  bone.  This  ne- 
crosis was  formerly  frequent  in  match  factories,  but  has  become  rarer 


PHOSPHORUS.  593 

since  amorphous  phosphorus  has  been  substituted  for  the  yellow  form,1 
and  since  greater  attention  has  been  paid  to  the  ventilation  of  the  fac- 
tories and  to  the  condition  of  the  teeth  of  the  employees.  Magitot  has 
recently  advanced  the  opinion  that  exposure  to  phosphorus  fumes 
gives  rise  to  a  mild  chronic  form  of  poisoning,  quite  aside  from  the 
necrosis,  which  is  comparatively  rare.  The  symptoms  are  cachexia, 
slight  jaundice,  anaemia,  and  abuminuria,  and  in  more  advanced  cases 
chronic  enteritis  and  diarrhoea,  bronchitis,  and  a  curious  fragility  of  the 
bones. 

Action :  Fatty  Degeneration. — A  very  striking  feature  in  phosphorus 
poisoning,  and  one  that  was  early  recognized  in  its  history,  is  the  ap- 
pearance of  numerous  fat  globules  in  the  cells  of  many  organs,  notably 
in  those  of  the  liver,  kidney,  gastric  and  intestinal  glands,  and  in  the 
muscle  fibres  of  the  heart,  stomach,  intestine,  smaller  arteries  and  often 
of  the  skeletal  muscles.  The  question  has  been  raised  whether  this  fat 
is  formed  by  the  degeneration  of  the  protoplasm  of  the  cells  in  which 
it  is  found,  or  whether  it  is  not  transported  from  other  parts  of  the 
body  and  only  deposited  in  these  cells,  the  school  of  Yoit  maintaining 
the  former  view,  while  Pfliiger  and  his  pupils  uphold  the  latter.  The 
advantage  at  present  seems  to  lie  with  Pfliiger,  who  has  shown  that 
the  total  fat  of  the  body  is  not  increased  by  phosphorus,  although  this 
has  been  met  by  Lindemann's  explanation  that  a  certain  amount  of  fat 
is  destroyed  during  the  intoxication,  and  that  if  more  fat  were  not 
formed  from  the  proteids  through  the  action  of  the  poison,  there  would 
be  found  a  marked  deficiency  at  death.  A  strong  argument  for 
Pfliiger's  view  is  adduced  by  Rosenberg,  who  found  that  when  an 
animal  has  been  fed  on  foreign  fats  (e.  g.,  a  dog  upon  mutton  suet)  and 
is  then  poisoned  with  phosphorus,  the  fat  found  in  the  liver  cells  is 
that  characteristic  of  the  food  and  not  that  of  the  poisoned  animal  as 
might  be  expected  if  it  were  derived  from  the  proteids.  The  question 
cannot  yet  be  said  to  be  determined,  although  the  burden  of  proof 
certainly  seems  to  rest  on  the  defenders  of  the  earlier  view  that  the  fat 
arose  from  the  degenerated  proteids  of  the  cells  in  which  it  is  found. 
The  fatty  degeneration  or  infiltration  sets  in  only  after  some  time,  and, 
in  fact,  accompanies  the  secondary  symptoms  for  the  most  part,  although 
the  cells  of  the  stomach  and  upper  part  of  the  intestine  suffer  sooner, 
and  the  beginning  of  this  process  is  probably  the  cause  of  the  early 
vomiting. 

In  phosphorus  poisoning,  as  in  other  instances  of  fatty  degeneration, 
the  process  commences  in  cloudy  swelling  of  the  cells  followed  by  the 
appearance  of  granules,  which  soon  develop  into  fat  globules.  Even- 
tually the  degenerated  cells  break  up  into  detritus. 

Another  feature  in  phosphorus  poisoning,  which  is,  however,  better 
seen  after  repeated  small  doses  than  after  a  single  large  one,  is  the 
Proliferation  of  the  Interstitial  Connective  Tissue  of  the  stomach,  liver 

lrThe  phosphorous  sesquisulphide  (P4S3),  recently  introduced  in  match  factories, 
seems  to  be  even  safer  than  red  phosphorus,  for  though  minute  quantities  of  the  ele- 
ment are  released  from  it  in  the  tissues,  these  are  too  small  to  induce  any  symptoms. 

38 


594  INORGANIC  SALTS,  ACIDS  AND  BASES. 

and  kidney,  which  finally  induces  typical  cirrhosis  of  these  organs.  It 
was  formerly  supposed  that  this  indicated  a  specific  irritant  action  of 
the  phosphorus  vapor  on  the  connective  tissue,  but  many  pathologists 
now  regard  this  proliferation  as  a  secondary  result  of  the  necrosis  of 
the  parenchyma  cells.  In  animals  poisoned  by  the  prolonged  adminis- 
tration of  small  quantities  of  phosphorus,  the  ordinary  effects  of  hepatic 
and  renal  cirrhosis  have  been  induced,  such  as  dropsy,  anaemia  and 
cachexia. 

Besides  the  cells  which  have  undergone  fatty  degeneration,  the  liver 
often  contains  numerous  microscopic  areas  of  necrotic  tissue  and  in 
other  parts  actively  dividing  parenchymatous  cells. 

When  very  minute  quantities  of  phosphorus  are  administered  to 
animals,  no  poisoning  results,  but  according  to  Wegner  a  specific 
action  on  the  Bones  is  induced,  especially  in  young  animals,  in  which 
the  bones  are  still  growing.  Thus,  in  young  rabbits,  quantities  of 
J0—J-  mg.  given  for  several  weeks  are  found  to  be  followed  by  char- 
acteristic changes  in  the  growth  of  the  long  bones,  apparently  in- 
duced by  the  phosphorus  acting  as  an  irritant  or  stimulant  to  the 
bone-forming  cells  (osteoblasts).  Wherever  cancellous  bone  is  being 
formed  from  cartilage,  phosphorus  is  stated  by  Wegner  to  cause  the 
deposit  of  a  layer  which  resembles  the  dense  bone  of  the  shaft  in 
the  normal  animal  in  general  appearance  and  also  histologically. 
This  layer  of  dense  bone  at  the  growing  point  is  at  first  the  only 
change  induced,  but  if  the  treatment  lasts  longer,  the  soft  cancellous 
bone  which  was  deposited  before  the  phosphorus  treatment  began, 
is  gradually  absorbed.  The  medullary  cavity  of  the  bone  is  thus 
enlarged,  and  may,  in  fact,  extend  into  the  epiphyses,  which  in  the 
normal  bone  are  filled  with  cancellous  tissue,  but  which  now  form  part 
of  the  much  lengthened  cavity.  Eventually  the  whole  of  the  cancel- 
lous bone  may  be  absorbed,  and  a  similar  process  of  absorption  begins 
in  the  bone  formed  at  first  under  phosphorus,  while  the  dense  deposit 
is  pushed  further  into  the  remaining  cartilage.  The  development  of 
bone  from  cartilage  is  not  the  only  process  affected,  however,  for 
Wegner  states  that  in  the  bone  deposited  from  the  periosteum  a  some- 
what similar  change  is  induced,  as  is  shown  by  its  becoming  denser 
and  by  the  Haversian  canals  being  much  contracted  in  size.  In  full- 
grown  animals  the  changes  in  the  bone  are  much  less  distinct,  but  the 
lamellae  of  the  spongy  tissue  are  said  to  be  thickened  by  phosphorus 
treatment,  and  in  the  fowl  Wegner  states  that  the  medullary  cavity  may 
be  completely  obliterated  by  the  deposition  of  hard  bone.  Wegner 
supposes  that  this  effect  on  bone  is  due  to  a  specific  action  on  the  bone- 
forming  cells,  analogous  to  that  which  he  observed  in  the  connective 
tissue  of  the  liver.  As  has  been  mentioned  already,  however,  the  cir- 
rhosis of  the  liver  in  chronic  phosphorus  poisoning  is  believed  by  many 
not  to  be  due  to  primary  irritation  of  the  interstitial  tissue,  but  to  be 
secondary  to  the  destruction  of  the  parenchymatous  cells,  so  that  this 
analogy  is  rendered  doubtful. 

Wegner  found  further  that  when  the  calcium  salts  were  withdrawn 


PHOSPHORUS.  595 

from  the  food  of  animals  treated  with  phosphorus,  the  exaggerated  ac- 
tivity of  the  bone-forming  cells  continued,  but  no  lime  was  deposited, 
so  that  the  bone  presented  the  appearance  of  rickets.  The  same  re- 
sult has,  however,  been  obtained  by  other  investigators  by  the  with- 
drawal of  calcium  without  phosphorus.  Kassowitz  took  up  the  inves- 

FIG.  50. 


A  B 

Section  of  the  head  of  the  femur  in  calf.    A,  normal,  B,  after  treatment  with  minute  doses  of 
phosphorus.     C,  the  cap  of  dense  bone  at  the  growing  point.     (After  WEGNKR.  ) 

tigation  some  twelve  years  later,  and  observed  the  layer  of  white  dense 
bone  described  by  Wegner  at  the  edge  of  the  ossifying  cartilage,  but 
regards  it  not  as  the  result  of  excessive  activity  of  the  osteoblasts,  but 
as  due  to  a  slower  absorption  of  the  calcified  cartilage  from  a  less  rapid 
extension  of  the  blood  vessels  than  is  normal.  With  large  doses  he 
produced  appearances  closely  resembling  those  of  rickets.  Several 
other  investigators  have  observed  changes  in  the  bones  after  phos- 
phorus, so  that  there  is  good  reason  to  believe  that  it  possesses  some 
specific  action  on  them,  although  some  writers  failed  to  obtain  definite 
results  and  of  those  who  observed  a  modification  in  the  growth  no  two 
agree  in  the  description  of  the  changes  or  in  their  interpretation.  This 
specific  action  on  the  bone-forming  tissues  and  particularly  on  the 
periosteum  has  been  used  by  Wegner  to  explain  the  necrosis  of  the 
jaw  in  match  factories.  He  supposes  that  the  phosphorus  vapor  reach- 
ing the  periosteum  of  the  jaw  through  a  carious  tooth  or  some  lesion 
of  the  gums,  excites  a  mild  periostitis,  which  in  turn  leads  to  the  for- 
mation of  new  layers  of  bone  around  the  jaw.  Necrosis  of  the  bones 
has  not  been  satisfactorily  demonstrated  in  animals  exposed  to  phos- 
phorus vapor,  although  numerous  experiments  have  been  performed 
with  the  object  of  studying  its  development.  The  view  of  the  latest 
investigators  is  that  microbial  infection  is  necessary  to  permit  of  the 
changes  observed  clinically,  but  that  phosphorus  induces  some  change 
in  the  bones  which  predisposes  them  to  infection  by  the  tubercle  ba- 


596  INORGANIC  SALTS,    ACIDS  AND  BASES. 

cillus  and  other  organisms  which  induce  necrosis.  The  occurrence  of 
necrosis  of  the  jaw  is  in  fact  a  strong  argument  for  the  correctness  of 
the  view  that  a  specific  action  on  bone  exists,  for  under  no  other  poison, 
even  when  much  more  irritant  vapor  is  inhaled,  does  a  similar  process 
occur  in  man.  The  exact  nature  of  this  action  on  bone,  and  its  rela- 
tion to  rickets  and  to  osteomalacia  must,  however,  be  left  for  further 
research  to  determine. 

Phosphorus  weakens  and  slows  the  Heart  when  it  is  applied  to  it 
directly  in  the  frog,  or  by  intravenous  injection  in  mammals.  In 
many  cases  of  acute  poisoning  in  man,  however,  the  heart  does  not 
seem  to  be  seriously  affected  until  very  late,  and  this  is  particularly  the 
case  when  comparatively  small  quantities  have  been  absorbed.  In 
those  cases  in  which  large  amounts  are  swallowed  in  solution  or  in  fine 
division,  and  in  which  death  occurs  before  any  secondary  symp- 
toms have  been  developed,  the  fatal  issue  is  generally  ascribed  to  the 
cardiac  action.  This  direct  action  on  the  heart  must  be  distinguished 
from  the  fatty  degeneration  of  the  cardiac  muscle,  which  is  seen  in  the 
later  stages  of  poisoning,  for  no  degeneration  of  the  heart,  and,  in  fact, 
no  pathological  changes  whatever,  may  be  found  in  those  rapidly  fatal 
cases.  Phosphorus  acts  on  the  heart  muscle  directly,  and  does  not 
seem  to  affect  the  regulating  nerves  in  any  way.  According  to  Pal, 
the  blood-pressure  is  lowered  in  some  cases  not  by  cardiac  action,  but 
by  the  dilation  of  the  vessels. 

The  Blood  is  but  little  changed  outside  the  body  by  phosphorus, 
for  though  Araki  states  that  the  haemoglobin  parts  with  oxygen  more 
slowly  than  usual,  the  difference  is  trifling.  In  many  cases  of  fatal 
poisoning,  the  blood  is  found  not  to  clot  so  readily  as  usual,  and  some- 
times to  remain  fluid  for  forty-eight  hours  or  more.  According  to 
Corin  and  Ansiaux  and  Jacoby  this  occurs  only  in  cases  in  which  the 
patients  live  for  several  days,  and  is  not  a  direct  effect  of  the  poison, 
but  is  due  to  the  changes  in  the  intestine  and  liver,  which  lessen  or 
entirely  destroy  the  fibrinogen.  Jacoby  states  that  the  blood  not  only 
fails  to  clot  but  is  capable  of  redissolving  fibrin  and  attributes  this  to 
the  presence  of  the  autolytic  ferment  of  the  liver. 

The  absence  of  clotting  in  the  blood  may  be  a  factor  in  the  haemor- 
rhages which  are  met  with  among  the  symptoms  of  the  second  stage, 
but  the  immediate  cause  of  these  is  the  fatty  degeneration  of  the  mus- 
cular coat  of  the  smaller  arteries  throughout  the  body.  These  changes 
in  the  blood  vessels  may  perhaps  explain  the  oedema  of  the  retina, 
which  is  seen  in  animals  poisoned  with  phosphorus,  though  these  have 
also  been  attributed  to  some  change  in  the  blood.  Occasionally  gan- 
grene of  the  extremities  has  been  observed  in  phosphorus  poisoning, 
probably  owing  to  the  changes  in  the  vessel  walls. 

Small  doses  of  phosphorus  generally  increase  the  number  of  the  red- 
blood  cells  in  man,  and  even  in  poisoning  a  sudden  or  gradual  increase 
in  these  may  occur,  along  with  a  diminution  of  the  leucocytes.  The 
haemoglobin  is  not  correspondingly  augmented,  however.  In  the  lower 
animals  the  effect  on  the  blood  cells  varies  a  great  deal ;  in  the  dog  an 


PHOSPHORUS.  597 

unusual  number  of  red  blood  cells  appears  to  be  destroyed  ;  in  the  rab- 
bit no  distinct  alteration  in  the  number  of  the  red  cells  but  some  leuco- 
cytosis  has  been  observed,  while  in  fowls  an  increase  in  the  leucocytes 
accompanies  a  marked  destruction  of  the  red  cells ;  in  the  frog  the 
number  of  red  cells  is  not  reduced. 

The  Bone-marrow  in  chronic  poisoning  is  at  first  hypera3mic,  the  fat 
cells  are  atrophied  and  the  leucoblasts  are  greatly  increased ;  later  a 
gelatinous  degeneration  sets  in  with  a  decrease  in  the  number  of  the 
marrow-cells  and  a  corresponding  increase  in  the  connective  tissue. 

The  peripheral  Nerves  and  Muscles  do  not  seem  to  be  affected  in 
phosphorus  poisoning,  except  in  so  far  as  the  latter  undergo  fatty  de- 
generation. An  excised  muscle  lives  almost  as  long  in  salt  solution 
containing  phosphorus  as  in  the  unpoisoned  solution. 

The  Central  Nervous  System  is  also  little  changed  by  phosphorus. 
The  coma  and  convulsions  which  appear  before  death  may  be  due 
rather  to  the  disordered  metabolism  than  to  any  direct  influence,  as  is 
shown  by  the  fact  that  consciousness  is  preserved  throughout  the  first 
stage,  and  as  a  general  rule  until  late  in  the  second. 

The  fatty  degeneration  of  the  epithelial  cells  of  the  Stomach  and 
Intestine  explains  the  abdominal  pain,  the  vomiting  and  the  occasional 
diarrhoea  seen  among  the  secondary  symptoms.  The  earlier  phases  of 
this  action  may  be  the  cause  of  the  vomiting  and  nausea  of  the  first 
stage.  This  degeneration  occurs  also  when  phosphorus  is  injected 
hypodermically,  and  is  therefore  of  the  same  nature  as  that  in  the 
other  organs.  The  cells  of  the  stomach  first  attacked  are  those  of  the 
glands,  and  the  condition  has  been  termed  gastradenitis. 

The  fatty  changes  in  the  Liver  cause  a  considerable  increase  in  the 
area  of  hepatic  dulness,  and  at  the  same  time  induce  some  pain  and 
tenderness  over  the  organ. 

The  icterus  of  phosphorus  poisoning  has  been  examined  by  Stadel- 
mann  in  dogs.  He  found  that  the  changes  in  the  bile  secretion  may  be 
divided  into  three  phases,  in  the  first  of  which  a  larger  amount  of  bile 
pigment  is  excreted  than  usual,  this  denoting  an  unwonted  activity  of 
the  liver  cells.  In  the  second  phase  the  bile  becomes  clouded,  is  less 
deeply  colored  and  more  viscous,  and  icterus  makes  its  appearance 
in  the  skin  and  conjunctiva.  The  secretion  in  this  stage  seems  to  be 
derived  largely  from  the  mucous  cells  of  the  smaller  bile  ducts,  and 
contains  comparatively  little  of  the  excretion  of  the  liver  cell  proper, 
In  the  third  phase,  which  is  that  of  recovery,  the  bile  loses  its  turbidity 
and  viscosity,  and  is  very  dark  in  color,  because  the  pigment  which 
was  deposited  in  the  tissues  during  the  second  stage  is  reabsorbed  and 
excreted  in  the  bile ;  the  jaundice  color  of  course  disappears  from  the 
skin  as  the  bile  pigment  is  reabsorbed.  The  bile  salts  are  also  very 
much  reduced  in  phosphorus  poisoning.  Stadelmann  attributes  these 
changes  to  the  bile  capillaries  being  rendered  less  pervious,  by  the  en- 
larged liver  cells  or  the  proliferating  connective  tissue  pressing  on  them 
and  narrowing  their  lumen.  This  prevents  the  bile  which  is  formed 
by  the  liver  cell  from  reaching  the  gall  bladder,  and  the  pigment  is 


598  INORGANIC  SALTS,  ACIDS  AND  BASES. 

therefore  absorbed  and  gives  rise  to  jaundice.  The  pale  viscous  fluid 
which  escapes  from  the  ducts  in  the  second  stage  is  probably  not  true 
liver  secretion,  but  mucus  from  the  ducts.  During  recovery,  the  hepatic 
cells  lessen  in  size,  the  pressure  on  the  bile  capillaries  is  relieved  and 
the  secretion  escapes,  while  the  pigment  which  was  distributed  through 
the  tissues  is  reabsorbed  and  excreted  by  the  ordinary  channel.  The 
jaundice  may  also  be  accounted  for  in  part  by  the  destruction  of  the 
red  cells  of  the  blood  and  consequent  increase  of  pigment  formation  in 
the  liver.  This  view  is  supported  by  the  fact  that  in  the  rabbit,  in  which 
the  red  cells  are  not  decomposed  by  phosphorus,  no  icterus  is  observed, 
while  in  the  dog,  in  which  some  of  the  cells  are  destroyed,  it  is  very 
marked.  In  man,  however,  there  is  no  evidence  that  the  red  cells  are  di- 
minished in  number,  yet  jaundice  is  one  of  the  commonest  symptoms. 
The  bile  very  often  contains  albumin  in  considerable  amount,  and  in 
the  later  stages  red  blood  cells  may  occur  in  it. 

In  addition  to  the  fatty  infiltration  of  the  cells  and  the  changes  in 
the  bile,  the  liver  has  been  shown  to  undergo  a  specific  alteration  in  its 
activity,  which  is  manifested  by  the  presence  of  large  quantities  of 
ammonia,  protagon,  jccorin,  leucin  and  tyrosin,  while  less  lecithin  than 
usual  is  present.  When  the  liver  of  an  unpoisoned  animal  is  kept 
from  putrefaction  for  some  time,  the  tissue  is  broken  down  by  the  ac- 
tion of  an  autolytic  ferment,  and  the  same  constituents  are  formed  in 
large  quantity ;  the  liver  in  phosphorus  poisoning  undergoes  the  same 
changes  when  preserved  from  putrefaction,  but  the  autolysis  progresses 
much  more  rapidly.  Jacoby  therefore  infers  that  phosphorus  aug- 
ments the  activity  of  the  autolytic  ferment  of  the  liver  and  thus  leads 
to  the  presence  in  the  living  organ  of  some  products  which  are  absent 
in  the  normal  one.  He  regards  the  disappearance  of  the  fibrinogen  of 
the  blood  as  a  further  effect  of  this  liver  autolysis,  for  he  found  that 
the  injection  of  the  autolytic  ferment  into  normal  animals  prevented 
coagulation. 

The  fatty  degeneration  of  the  Renal  Epithelium  may  account  in  part 
for  the  albuminuria,  which  is  not  generally  severe,  and  is  not  infre- 
quently absent  in  cases  of  poisoning.  Fatty  casts  and  even  globules 
of  fat  are  often  found  in  the  urine  in  cases  which  run  a  chronic  course. 
Blood  and  haemoglobin  may  also  appear  in  it  from  haemorrhages  into 
the  kidney.  The  other  changes  in  the  urine  are  not  referable  to  the 
renal  disease,  but  to  the  modification  of  the  general  metabolism  of  the 
tissues,  the  kidneys  merely  excreting  the  abnormal  products  of  decom- 
position which  appear  in  the  blood. 

These  abnormalities  in  the  Urine  have  been  examined  very  often, 
but  some  discrepancies  are  still  to  be  found  in  the  accounts  of  different 
authors.  The  urine  itself  is  often  somewhat  increased  in  quantity  in 
the  early  stages  of  the  intoxication,  but  afterwards  becomes  deficient, 
and  towards  death  complete  anuria  may  be  observed.  The  increased 
urine  is  probably  due  to  the  increase  of  the  urinary  substances  in  the 
blood,  while  the  diminution,  which  may  occur  early,  may  be  explained 
by  the  small  quantity  of  water  absorbed  from  the  stomach  and  intes- 


PHOSPHORUS.  599 

tine,  by  the  degeneration  of  the  secretory  cells,  or  by  the  failure  of  the 
circulation. 

The  nitrogen  of  the  urine  varies  considerably  in  different  cases. 
Very  often  in  the  first  few  days  after  the  ingestion  of  the  poison,  it  is 
markedly  diminished  in  amount,  but  this  is  not  due  to  any  specific 
action  of  the  poison,  but  to  the  prolonged  nausea  and  vomiting  which 
prevent  the  absorption  of  food ;  the  nitrogenous  excretion  thus  cor- 
responds to  that  during  the  first  few  days  of  starvation.  After  this, 
however,  a  very  considerable  increase  in  the  nitrogen  is  observed,  even 
although  the  patient  continues  to  fast.  In  the  course  of  starvation  a 
rise  in  the  nitrogen  excretion  also  occurs  after  some  time,  but  this  is 
never  so  great  as  that  seen  in  phosphorus  poisoning,  so  that  the  poison 
has  generally  been  credited  with  a  specific  action  increasing  the  waste 
of  the  nitrogenous  tissues.  The  excretion  of  urea  does  not  increase  in 
proportion  with  the  total  nitrogen,  in  fact  less  urea  is  often  excreted 
than  in  the  first  days  of  the  intoxication.  But  the  nitrogen  excreted  in 
the  form  of  ammonia  is  much  increased  in  man  and  the  dog,  while  it 
is  not  altered  in  the  rabbit.  This  excretion  of  ammonia  suggests  the 
formation  of  excess  of  acid  in  the  tissues,1  and  as  a  matter  of  fact  sar- 
colactic  acid  is  found  in  very  considerable  quantity  in  the  urine  in  man, 
the  dog  and  the  rabbit  in  phosphorus  poisoning.  The  increased  am- 
monia of  the  urine  is  therefore  to  be  referred,  at  any  rate  in  part,  to  the 
formation  of  this  acid  in  the  tissues,  and  if  fixed  alkalies  are  adminis- 
tered, the  ammonia  of  the  urine  falls  at  once  in  amount  because  the 
alkali  neutralizes  the  sarcolactic  acid. 

The  uric  acid  excreted  is  often  somewhat  increased  in  amount,  but 
on  the  whole  is  little  altered  by  phosphorus  in  man.  This  perhaps 
indicates  that  the  nuclei  of  the  cells  are  less  subject  to  the  action  of 
the  poison  than  the  cytoplasm,  and  this  is  supported  by  histological 
examination,  for  the  fat  globules  are  found  in  the  cell  body,  and  not 
in  the  nucleus. 

Some  increase  in  the  other  nitrogenous  constituents  of  the  urine  also 
occurs  in  phosphorus  poisoning,  and  a  number  of  amido-acids  have 
been  identified  in  it.  The  best  known  of  these  are  tyrosin  and  leucin 
crystals,  which  are  not  always  present  in  the  urine,  however,  although 
they  have  been  found  in  the  blood  in  some  quantity.  Baumann  found 
an  increase  in  the  substances  of  the  aromatic  series  in  the  urine.  Albu- 
min may  be  present  in  small  amount,  and  peptone  is  sometimes  ex- 
creted. 

The  chlorides  of  the  urine  are  much  reduced  in  amount,  owing  to 
the  patient  taking  little  or  no  food.  The  phosphates  of  the  urine  are 
often  very  considerably  augmented,  but  not  because  of  the  excretion 
of  phosphorus  as  phosphates,  for  the  quantity  absorbed  is  too  small  to 
cause  any  appreciable  change.  The  increase  in  the  phosphates  is 
rather  to  be  ascribed  to  an  augmented  waste  of  the  tissues,  and  the 
sulphates  are  also  excreted  in  larger  quantity  for  the  same  reason. 

When  icterus  is  present,  the  urine  may  be  dark  in  color  from  the 
1  See  Ammonia,  Acids,  pp.  551,  555. 


600  INORGANIC  SALTS,  ACIDS  AND  BASES. 

bile  pigment  excreted,  and  bile  acids  are  also  often  contained  in  it. 
Sarcolactic  acid  appears  in  considerable  quantity,  and  is  sometimes 
accompanied  by  some  sugar. 

Metabolism. — The  carbonic  acid  excretion  and  oxygen  absorption  by 
the  lungs  are  generally  found  to  undergo  comparatively  slight  changes 
in  phosphorus  poisoning,  while  all  the  evidence  points  to  grave  de- 
rangement in  the  proteid  metabolism.  Meyer  found  the  alkalinity  of 
the  blood  reduced  through  the  presence  of  lactic  acid  in  excess  in  the 
tissues,  and  this  has  the  further  effect  of  increasing  the  ammonia  of  the 
urine  ;  lactic  acid  is  also  found  in  the  stomach  along  with  hydrochloric 
acid.  It  is  believed  to  arise  from  the  glycogen  of  the  liver,  which 
is  much  reduced  in  amount.  This  lactic  acid  formation  has  been 
attributed  to  deficient  oxidation  in  the  tissues,  which  has  long  been 
held  to  be  one  of  the  fundamental  features  of  phosphorus  poisoning. 
In  addition,  the  nitrogenous  constituents  of  the  body  are  obviously 
destroyed  more  rapidly  than  usual,  for  unusually  large  amounts  of 
nitrogen  appear  in  the  urine ;  some  of  this  increase  may,  it  is  true,  arise 
from  the  acid  formation,  and  thus  indirectly  from  the  deficient  oxidation. 

More  recently  the  great  similarity  between  the  results  of  normal 
autolysis  and  of  phosphorus  poisoning  has  led  several  investigators  to 
believe  that  the  essential  effect  of  phosphorus  is  an  acceleration  of  the 
autolytic  process,  and  this  is  supported  \>y  the  results  obtained  by 
Jacoby  in  experiments  in  which  the  autolysis  of  the  normal  liver  was 
compared  with  that  of  the  liver  obtained  from  an  animal  poisoned 
with  phosphorus. 

Autolysis  or  destructive  metabolism  occurs  in  normal  living  cells, 
but  in  phosphorus  poisoning  it  is  supposed  to  proceed  more  rapidly, 
and  many  of  its  products  are  not  so  completely  decomposed  as  nor- 
mally, so  that  intermediate  products,  such  as  leucin,  tyrosin  and  other 
amido-acids,  appear  in  large  quantities  in  the  organs  and  often  in  the 
excretions  ;  lactic  acid  is  similarly  a  product  of  autolysis,  which  fails 
to  be  oxidized  to  carbonic  acid  as  in  the  normal  body.  This  accel- 
erated autolysis  occurs  not  only  in  the  liver  but  also  in  other  organs, 
although  in  a  less  marked  degree. 

It  was  formerly  believed  that  the  fatty  degeneration  was  dependent 
on  lessened  oxidation  ; l  that  the  fat  formed  by  the  decomposition  of 
the  proteids  could  not  be  oxidized  as  it  is  normally,  and  therefore 
remained  in  the  cell.  But  this  is  not  consistent  with  the  view  prevail- 
ing at  present,  that  the  accumulation  of  fat  in  the  liver  and  other 
organs  is  due  to  its  migration  from  other  parts  of  the  body,  so  that  the 
relation  between  the  two  phenomena  is  not  so  simple  as  has  been  sup- 
posed. It  seems  probable  that  the  fatty  degeneration  is  a  secondary 
result  of  the  accelerated  autolysis  ;  according  to  some  writers  (Wald- 
vogel)  the  fat  arises  from  the  proteids  in  the  process  of  autolysis,  but  it 

1  The  lessened  oxidation  in  the  tissues  was  at  one  time  believed  to  be  due  to  the 
phosphorus  using  up  the  oxygen  for  its  own  oxidation,  but  this  is  obviously  incorrect, 
for  the  amount  of  oxygen  required  for  this  would  be  quite  insignificant.  Another 
theory,  that  phosphorus  acts  by  liberating  nascent  oxygen  in  the  cells,  is  based  on  no 
sufficient  evidence. 


PHOSPHORUS.  601 

seems  more  plausible  to  suppose  that  the  cells  in  the  condition  of 
unwonted  activity  draw  upon  the  fat  already  present  in  the  tissues  and 
store  it  in  their  interior  in  the  form  of  globules. 

In  view  of  the  curious  effect  of  phosphorus  on  the  tissue  change  of 
the  vertebrates,  its  action  upon  simpler  forms  possesses  some  interest. 
It  has  been  found,  however,  that  yeast,  infusoria  and  bacteria  are  very 
little  affected  by  the  presence  of  this  poison,  and  living  microbes  are 
found  in  large  numbers  on  solid  pieces  of  phosphorus.  The  ferments 
are  also  unaffected  for  the  most  part,  pepsin  and  pancreatin  acting  in 
the  presence  of  phosphorus.  Curiously  enough,  although  the  oxida- 
tion is  imperfect  in  animals  poisoned  with  phosphorus,  Hauser  has 
found  that  if  phosphorus  be  added  to  the  blood  which  is  perfused 
through  an  excised  organ,  the  oxidation  is  as  rapid  as  if  no  poison  had 
been  added.  He  found,  however,  that  some  of  the  synthetic  processes 
of  the  body  were  probably  retarded  by  it,  for  less  hippuric  acid  was 
formed  in  a  kidney  perfused  with  blood  containing  phosphorus  than  in 
one  in  which  normal  blood  was  used.  On  the  other  hand  the  autolytic 
activity  of  the  liver  is  augmented,  as  has  been  noted  already. 

The  Temperature  is  often  low  in  the  later  stages  of  phosphorus 
poisoning,  but  slight  fever  is  also  observed  in  some  cases. 

The  Fate  of  phosphorus  in  the  body  is  still  obscure.  It  is  possible 
that  some  of  it  is  oxidized  to  phosphoric  acid,  and  some  phosphorus  is 
said  to  be  excreted  by  the  lungs,  although  the  statement  that  the  breath 
becomes  phosphorescent  seems  to  be  extremely  improbable.  It  is  also 
excreted  in  the  urine  in  some  organic  combinations,  of  which  nothing 
is  known,  though  they  are  said  to  be  volatile.  In  pregnant  animals 
poisoned  with  phosphorus,  the  'foetus  is  found  to  undergo  fatty  degen- 
eration, so  that  the  poison  would  seem  to  pass  through  the  placenta. 

Phosphuretted  hydrogen  (PH3)  induces  the  same  symptoms  as  phos- 
phorus, when  it  is  given  in  repeated  small  quantities.  Larger  doses 
are  very  rapidly  fatal  and  the  symptoms  differ  entirely  from  those  of 
phosphorus  poisoning,  consisting  of  marked  dyspnoea,  purgation,  weak- 
ness, tremor,  and  finally  violent  convulsions  and  respiratory  failure. 
The  oxygen  compounds  do  not  seem  to  have  any  such  effects,  and  for 
the  most  part  are  harmless  except  in  very  large  doses. 

PREPARATIONS. 

Phosphorus  (U.  S.  P.,  B.  P.),  a  translucent,  nearly  colorless  solid  resembling 
wax  in  lustre  and  consistency.  It  emits  white  fumes  in  the  air,  which  are 
luminous  in  the  dark,  and  takes  fire  spontaneously.  The  fumes  have  the 
odor  of  garlic,  and  in  dilute  solution  phosphorus  has  a  harsh,  disagreeable 
taste.  It  is  very  little  soluble  in  water,  more  so  in  alcohol,  and  dissolves  to 
about  two  per  cent,  in  fats  and  oils.  £-1  mg.  (r&n— 3*3  gr.)  (B.  P.  jiiff-sV  gr.)- 

Oleum  Phosphoratum  (B.  P.)  is  a  one  per  cent,  solution  in  almond  oil  and 
ether  (1-5  mins.).  Phosphorated  oil  ought  to  be  freshly  prepared  and  kept  in 
tightly  stoppered  bottles  ;  solutions  of  one  per  cent,  tend  to  lose  their  strength 
by  evaporation  of  the  phosphorus  and  by  oxidation,  when  the  bottle  contains 
air.  It  is  said  to  keep  better  in  more  dilute  solution  (one  per  mille).  It  is 
probable  that  much  of  the  oil  dispensed  is  under  one  per  cent,  in  strength. 

Pilulce  Phosphori  (U.  S.  P.),  each  pill  contains  0.6  mg.  of  phosphorus  (T^  gr.). 

Pilula  Phosphori  (B.  P.),  2  per  cent.,  1-2  grs. 


602  INORGANIC  SALTS,   ACIDS  AND  BASES. 

Therapeutic  Uses.  —  Phosphorus  has  been  recommended  in  various 
diseases  of  the  central  nervous  system  and  in  neuralgia,  but  it  is  still 
questionable  whether  it  is  of  any  real  benefit  in  these.  There  is  more 
reason  to  believe  in  its  virtues  in  bone  disease,  more  especially  in 
rachitis  and  osteomalacia,  for  in  a  number  of  instances  marked  im- 
provement has  been  observed  in  these  diseases  under  its  use.  It  is 
generally  given  in  solution  in  cod-liver  oil,  and  the  benefit  may  be  due 
in  part  to  the  menstruum,  but  not  entirely,  for  Sternberg  observed  a 
relapse  in  a  case  of  osteomalacia  when  pure  cod-liver  oil  was  substi- 
tuted for  the  phosphorated  oil.  In  rickets  a  solution  containing  0.01 
G.  in  100  c.c.  of  cod-liver  oil  is  recommended ;  2-4  teaspoonfuls  to 
be  given  each  day.1  In  osteomalacia  a  one  per  cent,  solution  may  be 
prescribed  and  1-5  mg.  phosphorus  taken  each  day. 

Rey  found  the  lime  excreted  in  the  urine  in  rickets  increased  under 
the  treatment  with  phosphorated  cod-liver  oil,  much  less  under  the  oil 
alone,  and  not  at  all  under  phosphorus  alone.  He  regards  this  as  in- 
dicating an  increased  absorption  of  lime  from  the  food.  Other  bone 
diseases,  such  as  caries  and  ununited  fractures,  have  also  been  treated 
with  phosphorus  occasionally,  but  the  results  have  not  been  recorded 
in  sufficient  numbers  to  allow  of  any  statement  as  to  the  efficacy  of  the 
treatment. 

Treatment  of  Phosphorus  Poisoning. — Phosphorus  is  comparatively 
slowly  absorbed  from  the  alimentary  canal,  so  that  in  the  early  stages 
an  attempt  ought  to  be  made  to  remove  it  by  emetics  or  the  stomach 
tube,  and  by  purges.  Fats  and  oils  must  be  avoided,  as  they  tend  to 
dissolve  the  poison  and  promote  its  absorption.  Phosphorus  has  been 
found  in  the  stools  three  days  after  its  ingestion,  and  a  sharp  purge 
may  therefore  be  of  use  up  to  this  time. 

Another  method  of  treatment  is  that  aiming  at  the  oxidation  of  the 
phosphorus  in  the  stomach,  or  at  the  formation  of  unabsorbable  com- 
pounds. Turpentine  oil  was  formerly  used  with  the  object  of  oxidizing 
the  phosphorus  or  of  forming  some  compound  with  it  in  the  stomach, 
but  this  treatment  has  proved  quite  valueless  (Plavec).  Sulphate  of 
copper  is  recommended  in  phosphorus  poisoning,  a  large  dose  being 
given  first  as  an  emetic,  and  afterwards  smaller  doses  to  form  an  insolu- 
ble compound,  copper  phosphide.  Permanganate  of  potassium  solu- 
tion, one  per  roille,  has  been  recently  advised  to  oxidize  the  phosphorus, 
while  peroxide  of  hydrogen  solution  is  of  less  value.  In  the  secondary 
stage  alkalies  are  recommended  in  order  to  neutralize  the  excess  of 
sarcolactic  acid  formed  in  the  tissues. 

Phosphorus  necrosis  has  to  be  treated  surgically  on  the  same  princi- 
ples as  other  necroses  of  bone. 

1  This  would  be  equivalent  to  J-2  mg.  of  phosphorus  daily,  but  as  a  matter  of  fact 
the  phosphorated  oil  from  which  the  prescription  is  filled  contains  much  less  than  one 
per  cent.,  so  that  the  dose  actually  taken  probably  seldom  amounts  to  more  than  one 
milligram  daily. 


ARSENIC.  603 

BIBLIOGRAPHY. 

Wegner.     Virchow's  Arch.,  Iv.,  p.  11. 
Kassou-itz.     Ztschr.  f.  klin.  Med.,  vii.,  p.  36. 
Sternberg.     Ibid.,  xxii.,  p.  265. 

Stubenrauch.     Arch.  f.  klin.  Chir.,  lix.,  p.  144  ;  Ixi.,  p.  547. 
Jacoby.     Zeitschr.  f.  physiol.  Chem.,  xxx.,  p.  174. 
Mivau.  Stoeltzer.     Jahrb.  f.  Kinderheilkunde,  xlvii.,  p.  153. 
Rey.     Deutsch.  med.  Woch.,  1895,  p.  569. 
Stadelmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxiv.,  p.  270. 
Aufrecht.     Deutsch.  Arch.  f.  klin.  Med.,  xxiii..  p.  331. 
Ackermann.     Virchow's  Arch.,  cxv.,  p.  216. 
Stolnickow.     Arch.  f.  Anat.  u.  Phys.,  1887.     Supplement,  p.  1. 
Schidtze.     Virchow's  Arch.,  cii.,  p.  299. 
Meyer.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiv.,  p.  313. 
Pal     Wien.  klin.  Woch.,  ix.,  p.  999. 
Sehni.     Arch.  f.  Pharmacie,  ccxvii.,  p.  253. 

Plavec.     Arch.,  f.  exp.  Path.  u.  Pharm.,  xlviii.,  p.  150 ;  Pillager's  Arch.,  civ.,  p.  1. 
Miura.     Virchow's  Arch.,  xcvi.,  p.  54. 
Bauer.     Ztschr.  f.  Biol.,  vii.,  p.  63 ;  xiv.,  p.  527. 
Schultzen  u.  Riess.     Annalen  der  Charite,  xv.,  p.  1. 

Fraenkel     Berl.  klin.  Woch.,  1878,  p.  265 ;  Virchow's  Arch.,  Ixvii.,  p.  278. 
Falck.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii.,  p.  376. 
Waldvogel.     Virchow's  Arch.,  clxxvii.,  p.  1. 
Fraenkel  u.  Rohmann.     Ztschr.  f.  physiol.  Chem.,  iv.,  p.  439. 
Leo.     Ibid.,  ix.,  p.  469. 
Araki.     Ibid.,  xvii.,  p.  311 ;  xix.,  p.  422. 
Munzer.     Deutsch.  Arch.  f.  klin.  Med.,  lii.,  p.  199. 
Taussig.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxx.,  p.  161. 
Hauser.     Ibid.,  xxxvi.,  p.  165. 
Pilzecker.     Ztsch.  f.  physiol.  Chem.,  xli.,  p.  157. 
Oorin  u.  Ansiaux.    Vierteljahr.  f.  ger.  Med.,  1894,  i.,  pp.  80,  212. 
Lebert  et  Wyss.     Arch.  gen.  de  MM.,  1868,  ii.,  p.  257. 
Athanasiu.    Pfl  tiger's  Arch.,  Ixxiv.,  p.  511. 

Taylor.     Journ.  of  Exp.  Med.,  iv.,  p.  399 ;  Journ.  of  Med.  Research,  ix. 
Stockman  and  Charter  is.     Journ.  of  Path,  and  Bact.,  1903,  p.  205. 
Thayer  and  Wolf.     Journ.  of  Med.  Research,  ix.,  pp.  191,  216. 
Santesson.     Skand.  Arch,  f,  Phys.,  xv.,  pp.  259,  420. 
Jokote.     Arch  f.  Hygiene,  xlix,,  p.  275. 
Rosenfeld.     Cong.  f.  inn.  Med.,  xv.,  p.  427. 

Lindemann.  Arch.  f.  exp.  Path.  u.  Pharm.,  xli.,  p.  191.  Ztschr.  f.  Biol.,  xxxix., 
p.  1. 

Steinhaus.     Ziegler's  Beitriige  z.  path.  Anatomie,  xxii.,  p.  466. 
Monti,  Slick,  Frdnkel,  Zwei/el,  Kassowitz.     Wiener  klin.  Woch.,  1901. 

XXXI.    ARSENIC. 

Some  of  the  less  active  preparations  of  arsenic,  such  as  the  sul- 
phides, Realgar  (As2S2)  and  Orpiment  (As2S3),  have  been  known  in 
therapeutics  since  the  beginning  of  the  Christian  era,  but  this  metal 
was  brought  into  especial  prominence  in  later  times  through  the  fre- 
quent use  of  the  more  dangerous  oxides  in  criminal  poisoning.  Thus 
the  notorious  Aqua  Tofana  of  the  sixteenth  and  seventeenth  centuries 
owed  its  activity  to  the  presence  of  arsenic,  and  various  arsenical  com- 
pounds have  been  used  up  to  the  last  few  years  more  largely  than  al- 
most any  other  poison  in  suicide  and  homicide.  This  is  to  be  ex- 
plained by  their  having  been  widely  employed  in  the  arts,  and  thus 
being  readily  accessible  to  all,  and  by  the  general  recognition  of  their 
poisonous  nature.  Of  late  years  intentional  arsenic  poisoning  has  be- 
come somewhat  less  common,  though  on  the  other  hand,  accidental 
poisoning  is  still  met  with  not  infrequently,  especially  in  the  chronic 


604  INORGANIC  SALTS,   ACIDS  AND  BASES. 

forms.  Many  of  these  chronic  cases  are  extremely  difficult  to  diagnose, 
and  probably  often  pass  unrecognized  by  the  attending  physician.  In 
view  of  this  fact  it  seems  desirable  that  more  stringent  measures  should 
be  taken  to  reduce  the  use  of  arsenic  in  the  arts,  and  especially  to  pre- 
vent its  being  brought  in  contact  with  food.  The  danger  of  the  use 
of  the  green  arsenical  dyes,  such  as  Scheele's  Green  (arsenite  of  cop- 
per), and  Schweinfurt's  Green,  or  Paris  Green  (arsenite  and  acetate 
of  copper),  is  now  generally  recognized,  but  arsenic  is  still  used  in  the 
preparation  of  other  colors,  and  these  may  give  rise  to  poisoning  from 
the  imperfect  removal  of  the  metal.  It  has  also  been  used  in  dilute 
solution  to  preserve  food,  and  a  solution  is  often  sprayed  upon  grape 
vines  and  other  plants  to  preserve  them  from  the  attacks  of  insects. 
Poisoning  has  occurred  from  these  sources  and  is  difficult  to  diagnose, 
as  it  is  in  some  cases  impossible  to  find  the  means  by  which  the  arsenic 
enters  the  system.  A  widespread  epidemic  of  poisoning  in  England 
in  1900  drew  attention  to  a  source  of  arsenic  which  had  not  up  to  that 
time  received  the  attention  it  merited.  Several  thousands  of  persons 
suffered  from  arsenic  being  contained  in  cheap  beers  made  from  glu- 
cose, in  the  manufacture  of  which  sulphuric  acid  had  been  employed. 
The  sulphuric  acid  was  formed  from  iron  pyrites  containing  arsenic, 
and  the  poison  was  carried  from  the  sulphuric  acid  with  the  glucose 
into  the  beer.  Sulphuric  acid  is  used  in  the  manufacture  of  so  many 
drugs,  foods  and  other  substances  in  constant  use,  that  this  intimation 
that  it  may  convey  arsenic  into  articles  where  its  existence  has  not 
hitherto  been  suspected,  is  of  the  gravest  importance. 

Metallic  arsenic  is  insoluble  in  water,  and  passes  through  the  alimen- 
tary canal  for  the  most  part  unchanged  and  without  action,  but  it  is 
possible  that  small  quantities  may  be  oxidized  to  arsenious  acid  in  the 
stomach  and  intestine  under  some  conditions.  Some  symptoms  have 
been  observed  when  it  is  rubbed  on  the  skin  in  a  state  of  fine  division, 
and  these  are  probably  due  to  its  absorption  in  the  form  of  an  oxide. 
The  characteristic  "  arsenic  "  action  is  induced  by  the  salts  of  arsenious 
acid  (AsO3H3),  and  by  its  anhydride  (As2O3)  which  is  often  known  as 
arsenic,  and  which  exists  in  the  tissues  as  arsenites.  Arsenic  action  is 
therefor0  due,  not  to  the  element,  but  to  the  ion  of  arsenious  acid. 
The  anhydride  ^nd  salts  of  arsenic  acid  (H3AsO4)  cause  similar  symp- 
toms, but  are  lest  poisonous  and  act  more  slowly  than  those  of  arse- 
nious acid,  and  may  probably  owe  their  effects  to  the  formation  of 
arsenites  in  the  tissues. 

The  action  being  due  to  the  ion  and  not  to  the  element,  it  necessarily  fol- 
lows that  compounds  from  which  the  ion  is  not  liberated,  do  not  induce  the 
arsenic  action,  or  do  so  only  when  they  are  changed  to  bodies  which  can 
dissociate  the  arsenious  acid  ion.  Thus  organic  arsenic  combinations  in 
which  the  metallic  atom  is  directly  attached  to  carbon  are  only  feebly  poison- 
ous, but  in  course  of  time  seem  to  be  changed  to  arsenious  acid  in  the  tissues, 
and  then  cause  typical  poisoning.  The  best  known  of  these  are  cacodylic 
oxide  ((CH3)2As2O(CH3)2)  and  cacodylic  acid  ((CH3)2AsOOH).  Arsenical 
compounds  of  the  aromatic  series  have  also  been  examined  pharmacologically 
and  induce  arsenic  symptoms  when  given  in  large  quantities.  This  poison- 
ous action  is  again  due  not  to  the  undecomposed  molecule,  but  to  the  arseni- 
ous acid  derived  from  it,  some  of  which  is  found  excreted  in  the  urine. 


ARSENIC.  605 

Arsenious  acid,  which  in  the  following  pages  will  be  taken  as  the 
representative  of  "  arsenic  "  action,  has  a  somewhat  sweetish  taste,  and 
is  therefore  not  so  likely  to  be  detected  by  the  victim  as  many  of  the 
other  poisons. 

Symptoms.  —  In  large  quantities  arsenic  very  often  causes  no  symp- 
toms for  half  an  hour  or  more,  but  then  the  patient  complains  of  a 
feeling  of  constriction  in  the  throat,  of  difficulty  in  swallowing,  and 
of  discomfort  in  the  stomach  region.  This  soon  increases  to  violent 
pain,  and  is  accompanied  by  vomiting,  and  later  by  watery  diarrhoea. 
The  stools  are  at  first  of  ordinary  diarrhceic  appearance,  but  later  re- 
semble the  "  rice-water  "  stools  of  cholera,  in  that  they  consist  almost 
entirely  of  minute  shreds  of  disintegrated  mucous  membrane  suspended 
in  a  serous  fluid  ;  sometimes,  however,  they  are  clear  and  gelatinous 
in  appearance.  In  some  cases,  blood  appears  in  the  vomited  matter 
and  also  in  the  stools,  but  this  is  not  by  any  means  an  invariable  fea- 
ture. The  urine  is  diminished,  or  entirely  suppressed,  from  the  great 
amount  of  fluid  eliminated  by  the  stomach  and  bowel.  These  symp- 
toms from  the  alimentary  tract  are  accompanied  by  giddiness,  cramps 
in  the  muscles,  headache,  and  soon  by  collapse,  with  cold,  damp  skin, 
pallor,  feeble  pulse  and  weak,  sighing  respiration  ;  this  later  passes  into 
coma,  and  death  follows  with  or  without  convulsions.  In  cases  in 
which  the  dose  is  smaller  than  the  fatal  one,  or  in  which  much  of  the 
poison  is  eliminated  by  vomiting,  the  patient  may  recover  without 
further  symptoms  than  those  already  described.  Frequently,  how- 
ever, he  recovers  from  the  acute  symptoms  only  to  develop  those  of 
chronic  arsenical  poisoning.  In  some  instances  it  is  said  that  no 
symptoms  are  present  except  those  of  collapse  and  coma.  In  acute 
poisoning  death  may  occur  within  24  hours,  but  more  frequently  the 
patient  lives  for  2—4  days  or  longer,  and  then  succumbs  to  exhaustion. 
The  fatal  dose  is  very  uncertain,  because  arsenic  is  very  insoluble,  and 
much  of  the  poison  may  be  thrown  up  by  vomiting,  or  pass  out  in  the 
stools  unabsorbed.  Thus  in  some  cases,  recovery  has  followed  after 
very  large  quantities,  while  in  others  about  0.1  G.  (1 J  grs.)  has  proved 
fatal. 

Chronic  Arsenic  Poisoning  may  arise  from  a  single  large  dose,  the 
effects  persisting  for  weeks  or  months  after  the  ingestion  and  new  symp- 
toms arising  as  the  earlier  ones  disappear ;  more  frequently,  however, 
it  is  induced  by  the  prolonged  absorption  of  small  quantities.  The 
milder  symptoms  may  arise  from  its  therapeutic  use,  but  typical  cases 
are  generally  due  to  the  presence  of  arsenic  in  the  form  of  dyes  in  wall 
paper  or  clothes,  or  in  stuffed  animals  in  the  rooms  inhabited  by  the 
victims,  or  to  the  constant  handling  of  arsenical  pigments  and  other 
compounds  in  mines  and  manufactories.  Widespread  poisoning  has 
been  observed  from  the  use  of  wines  containing  arsenic  at  Hyeres  in 
France,  from  milk  diluted  with  arsenical  water  in  London,  and  from 
beer  in  the  Manchester  district.  In  these  last  cases  the  arsenic  was  in 
solution,  but  it  often  seems  to  be  inhaled  in  the  form  of  fine  dust,  which 
falls  from  the  walls  or  other  objects.  It  has  been  suggested  that  the 


606  INORGANIC  SALTS,  ACIDS  AND  BASES. 

arsenic  dyes  are  decomposed  by  microbes  and  the  volatile  arseniuretted 
hydrogen  (AsH3)  inhaled,  but  there  seems  no  reason  to  suppose  that 
this  is  the  case,  and  the  inhalation  of  fine  particles  is  a  sufficient  ex- 
planation. 

The  symptoms  of  chronic  arsenic  poisoning,  which  are  often  very 
obscure,  may  be  divided  into  three  phases.  ^  In  the  Jurst  of  these,  the 
patient  complains  of  weakness  and  languor,  loss  of1  appetite,  some  nausea 
and  occasionally  vomiting,  with  a  sense  of  heaviness  and  discomfort  in 
the  stomach.  Diarrhoea  may  be  present,  but  is  often  absent,  and  in 
fact  some  constipation  may  occur. 

In  the  second  phase  the  conjunctiva  is  often  red  and  inflamed,  and 
^oT^coryza  appear,  with  sneezing,Tioarseness  and  coughing, 
from  a  catarrhal  condition  of  the  mucous  membranes  of  the  nose  and 
larynx.  Some  swelling  of  the  liver  and  jaundice  may  occur,  but  these 
are  not  generally  well  marked.  Skin  eruptions  of  various  forms  —  pap- 
ular, vesicular,  or  erythematous  —  are  generally  noted  ;  very  often  the 
epidermis  falls  off  in  fine  brownish  scales,  or  in  tho  hands  and  feet  in 
large  flakes  (keratosis)  ;  a  curious  pigmentation  is  very  common,  the 
skin  assuming  a  dark  metallic  color  resembling  in  extreme  forms  that 
produced  by  rubbing  a  lead  pencil  upon  it  (arsenic  melanosis).  This 
pigmentation  is  much  more  marked  in  persons  of  dark  complexion  than 
in  fair  people  in  whom  it  may  be  indistinguishable  from  ordinary  freck- 
les ;  it  generally  disappears  when  the  patient  is  removed  from  the  poi- 
sonous atmosphere,  but  has  been  permanent  in  some  cases.  In  pro- 
longed poisoning  the  eruptions  may  simulate  almost  any  form  of  skin 
disease,  and  the  hair  and  nails  fall  off.  Herpes  is  not  infrequently 
observed  and  points  to  nervous  disturbances  such  as  are  prominent 
features  in  the  next  phase. 

These  phases  are  not  always  distinct  in  cases  of  poisoning,  and  very 
often  some  of  the  symptoms  of  the  second  phase  may  appear  before 
any  marked  disorder  of  the  digestive  tract.  In  the  prolonged  thera-  | 
peutic  use  of  arsenic,  the  first  indications  of  commencing  poisoning  are 
redness,  suffusion  and  swelling  of  the  conjunctiva  and  eyelids,  and 
dryness  of  the  nose  and  throat,  as  in  coryza.  On  the  other  hand,  in 
workmen  exposed  to  arsenical  dust,  the  first  symptoms  may  arise  from 
the  skin  or  from  bronchial  irritation. 

?  The  third  phase  is  marked  by  disturbance  of  sensation  and  motion  in 
localized  areas,  generally  in  the  hands  and  feet  (peripheral  neuritis). 
It  is  often  ushered  in  by  intense  persistent  headache  or  by  acute 
pain  located  around  the  knee,  ankle  or  foot,  less  frequently  in  the 
wrist  and  hand.  The  patient  complains  of  formication  in  the  ex- 
tremities, and  of  the  discomfort  caused  by  the  pressure  of  the  bed- 
clothes on  the  feet  and  legs.  The  palms  of  the  hands  and  the  soles  of 
the  feet  are  often  red,  swollen  and  extremely  sensitive  to  touch  (ery- 
thromelalgia),  and  pressure  on  the  muscles  induces  the  most  intense 
pain.  Later,  sensory  paralysis  may  set  in,  especially  in  the  extrem- 
ities, and  the  less  acute  sense  of  touch  in  the  feet  and  hands  induces 
symptoms  resembling  those  of  locomotor  ataxia.  The  sensitiveness  to 


AKSENIC.  607 

heat  and  cold  may  be  exaggerated  or  dulled,  or  sometimes  heat  is  not 
appreciated,  while  cold  causes  intense  pain.  The  sense  of  pain  varies 
in  different  cases,  in  some  being  abnormally  acute,  in  others  deadened. 
These  sensory  disturbances  are  followed  in  severe  poisoning  by  motor 
paralysis  which  generally  appears  in  the  extensor  muscles  of  the  toes, 
later  in  the  peronei  muscles.  More  rarely  the  flexor  muscles  of  the  leg 
and  foot  are  involved,  and  in  some  cases  the  affection  commences  in  the 
extensors  of  the  hand  and  fingers.  As  a  general  rule  the  paralysis  is 
confined  to  the  extremities,  but  in  some  cases  it  has  been  found  to  in- 
vade the  trunk.  It  is  generally,  but  not  invariably,  symmetrical,  and 
the  muscles  affected  atrophy  rapidly,  and  contract  weakly  to  the  gal- 
vanic shock,  not  at  all  to  the  faradic  except  in  the  beginning  of  the 
affection.  This  lessened  excitability  of  the  muscles  sometimes  appears 
before  the  typical  degeneration  reaction  is  observed,  but  is  then  fol- 
lowed by  it  later.  The  muscles  are  abnormally  excitable  to  mechanical 
stimulation,  however,  while  the  tendon  reflexes  are  generally  entirely 
absent.  There  is  sometimes  some  difficulty  experienced  in  diagnosing 
arsenic  from  lead  paralysis,  but  in  the  former  there  is  often  a  history 
of  acute  poisoning,  while  the  latter  is  almost  invariably  due  to  pro- 
longed absorption.  JDisturbances  of  sensation  are  much  more  com- 
mpjiJELarsenic  than  in  lead  palsy,  and  jn  the  latter  the  forearm  mus- 
cles are  generally  affected  first,  in  the  former  those  of  the  leg.  In 
arsenic  poisoning  atrophy  is  said  to  occiif  much  more  rapidly,  and 
there  is  no  line  on  the  gums.  Another  condition  which  presents  still 
greater  difficulties  in  diagnosis  is  alcoholic  neuritis.  But  in  the  latter 
skin  eruptions  are  extremely  rare,  coryza  is  not  present,  and  there  are 
generally  more  marked  brain  symptoms  than  in  arsenical  cases.  In 
doubtful  cases  the  urine  and  the  hair  of  the  patient  should  be  tested  for 
arsenic. 

Arsenic  paralysis  may  appear  as  early  as  three  days  after  an  acute 
intoxication,  but  is  commonly  observed  later  and  may  occur  only  after 
3-4  weeks.  Some  authors  have  asserted  that  in  chronic  arsenic  poi- 
soning there  is  a  paralysis  of  the  sexual  powers  (anaphrodisia),  and 
ascribe  this  to  an  action  on  the  nerves  of  the  sexual  organs,  similar  to 
that  observed  in  the  extremities,  but  this  symptom  is  not  by  any 
means  generally  present,  and,  in  fact,  abnormal  sexual  excitement  has 
been  noted  in  some  cases. 

In  very  prolonged  arsenic  poisoning  the  patient  may  sink  into  an 
apathetic,  semi-idiotic  condition,  or  may  become  epileptic.  In  most 
cases  the  symptoms  slowly  disappear  when  the  poison  is  removed,  but 
even  slight  paralysis  may  last  for  many  years  before  it  is  entirely 
cured,  and  after  complete  degeneration  of  the  muscles  little  improve- 
ment is  to  be  expected.  The  contractures  which  follow  are  generally 
due  to  the  unopposed  action  of  the  sound  muscles,  but  sometimes  arise 
from  the  shortening  of  the  paralyzed  ones. 

Arsenic  poisoning  generally  occurs  from  the  inhalation  of  particles 
of  the  drug,  or  from  swallowing  solutions  or  powders.  But  the  same 
symptoms  have  been  elicited  in  animals  by  subcutaneous  or  intravenous 


608  INORGANIC  SALTS,  ACIDS  AND  BASES. 

injection,  and  some  cases  of  poisoning  in  man  are  recorded  in  which 
the  arsenic  gained  entrance  to  the  body  through  its  application  to  burns 
or  other  surfaces  denuded  of  skin,  or  from  its  application  to  mucous 
membranes,  as  in  the  vagina. 

Action. — The  symptoms  of  arsenic  poisoning,  as  far  as  the  Alimen- 
tary Canal  is  concerned,  resemble  those  of  corrosive  poisoning  so  closely 
that  it  was  long  supposed  that  arsenic  had  some  destructive  effect  upon 
albumins,  resembling  that  of  the  acids  and  corrosive  metals.  Many 
attempts  to  form  a  combination  between  proteids  and  arsenic  have 
been  made,  but  have  proved  fruitless ;  arsenites  and  arsenious  acid  do 
not  coagulate  proteids  or  change  them  in  any  way,  except  when  applied 
in  such  enormous  quantities  as  never  reach  the  stomach. 

The  action  of  arsenic  on  the  alimentary  canal  cannot  be  explained 
as  due  to  any  ordinary  form  of  corrosion,  therefore,  although  the  symp- 
toms and  the  post-mortem  appearances  resemble  in  many  points  those 
of  the  corrosive  poisons.  Thus  the  mucous  membrane  of  the  stomach 
is  generally  found  red  and  swollen,  either  in  patches  or  throughout  its 
whole  extent.  Hemorrhages  into  it  are  occasionally  present,  but  are 
not  by  any  means  a  constant  feature,  and  little  or  no  erosion  can  be 
made  out  as  a  general  rule.  The  epithelial  coat  can  be  rubbed  off 
very  easily,  and  is  found  to  be  in  a  state  of  fatty  degeneration.  It 
sometimes  resembles  a  false  membrane  and  has  been  described  as  such, 
but  closer  examination  shows  it  to  consist  almost  entirely  of  the  degen- 
erated epithelium.  This  destruction  of  the  epithelium  is  often  con- 
fined to  particular  parts  of  the  organ,  affecting  the  posterior  wall 
chiefly  in  man.  Where  arsenic  has  been  swallowed  in  powder,  and 
has  remained  in  contact  with  the  wall  for  some  time,  the  congestion  is 
often  more  marked,  and  here  even  erosion  may  appear.  In  some  cases 
no  congestion  of  the  stomach  is  met,  the  only  lesion  consisting  in 
cloudy  swelling  and  fatty  degeneration  of  the  gland-cells,  similar  to 
that  mentioned  under  phosphorus. 

The  intestine  presents  very  similar  appearances,  the  mucous  mem- 
brane being  swollen  and  congested,  more  especially  around  Peyer's 
patches.  It  contains  a  quantity  of  thin  fluid  with  flakes  of  membrane, 
resembling  exactly  the  rice-water  stools  of  cholera,  and  in  fact  it  may 
be  difficult  to  distinguish  the  intestine  of  arsenic  poisoning  from  that  of 
cholera.  Small  particles  of  arsenic  are  often  found  in  the  stomach  and 
bowel,  even  after  profuse  vomiting  and  purging. 

In  some  cases  the  redness  a^d  congestion  extends  up  to  the  throat 
and  causes  a  feeling  of  soreness  in  the  mouth. 

The  first  explanation  suggested  for  the  action  of  arsenic  on  the  ali- 
mentary tract,  namely,  the  corrosive  action  of  the  drug,  has  been 
shown  to  be  incorrect,  for  the  same  symptoms  arise  when  arsenic  is 
absorbed  from  the  subcutaneous  tissue,  or  from  the  broken  skin.  This 
does  not  entirely  preclude  the  corrosive  action,  for  arsenic,  though  ab- 
sorbed from  the  skin,  may  be  excreted  by  the  mucous  membranes,  and 
thus  corrode  them ;  and,  as  a  matter  of  fact,  small  quantities  (up  to  a 
milligram)  have  been  isolated  from  the  stomach  and  intestines,  when 


ARSENIC.  609 

arsenic  was  injected  intravenously  in  animals,  but  these  are  obviously 
insufficient  to  cause  such  violent  symptoms.  Besides,  as  has  been 
stated,  arsenic  does  not  change  proteids  in  solution  as  the  corrosive 
poisons  do,  and  cannot  therefore  elicit  typical  corrosion.  Boehm 
and  his  pupils  have  suggested  that  the  gastro-intestinal  action  of 
arsenic  is  due,  not  to  any  direct  action  on  the  epithelium,  but  to  the 
vascular  changes  induced  by  it.  They  suppose  that  the  extreme  dila- 
tation of  the  intestinal  vessels  and  capillaries  gives  rise  to  the  conges- 
tion and  swelling,  and  this  in  turn  to  the  destruction  of  the  lining 
membrane,  perhaps  by  the  exudation  of  fluid  beneath  the  epithelium. 
This  transudation  of  fluid  is  certainly  in  accord  with  the  watery  char- 
acter of  the  stools  in  arsenic  poisoning,  but  the  explanation  does  not 
Beem  entirely  satisfactory,  for  it  fails  to  account  for  the  fatty  degener- 
ation and  the  cloudy  swelling  of  the  epithelium,  which  are  in  some 
cases  the  only  lesions  found  here.  The  fatty  degeneration  is  not  con- 
fined to  the  stomach  and  bowel,  but  involves  a  number  of  other  organs, 
although  it  is  not  as  a  general  rule  so  widely  distributed  as  in  phos- 
phorus poisoning.  Arsenic  then  must  be  considered  to  have  a  specific 
action  in  causing  fatty  degeneration  of  the  epithelium  of  the  stomach 
and  intestine.  This  in  itself  is  sufficient  to  explain  many  of  the 
symptoms  from  these  organs,  although  it  may  well  be  that  the  vascular 
action  is  the  cause  of  the  excess  of  fluid  in  the  intestine,  and  in  fact, 
the  fatty  degeneration  alone  is  insufficient  to  explain  this  feature,  which 
is  absent  in  phosphorus  poisoning.  In  cases  of  poisoning  where  the 
arsenic  is  taken  by  the  mouth,  and  especially  when  large  quantities  of 
dry  arsenious  acid  are  swallowed,  the  specific  action  on  the  epithelium 
and  the  vascular  action  are  probably  intensified  by  the  direct  contact 
of  the  poison.  Filehne  is  disposed  to  regard  the  corrosion  of  the 
stomach  which  is  sometimes  observed,  as  due  to  the  digestion  of  the 
epithelium  killed  by  arsenic,  and  not  to  the  direct  action  of  the 
poison. 

In  therapeutic  doses  arsenic  is  said  to  increase  the  appetite  and  pro* 
mote  digestion,  an  effect  which  may  perhaps  be  due  to  the  specific  ac-> 
|tion  on  the  epithelium,  this  in  its  milder  forms  proving  of  advantage* 
*to  the  organ,  though  in  excess  it  leads  to  its  degeneration. 

The  action  of  arsenic  on  the  Circulation  has  been  investigated  by 
several  authors,  who  have  obtained  discordant  results.  In  the  frog 
the  heart  is  slow  and  weak,  eventually  becomes  irregular,  and  ceases 
in  diastole  after  comparatively  small  doses ;  the  action  seems  to  be  a 
direct  paralysis  of  the  muscle.  In  the  mammal  the  heart  is  less 
affected  ;  it  is  somewhat  accelerated  by  very  small  doses  injected  in- 
travenously, but  is  slowed  by  larger  ones,  and  the  inhibitory  mechan- 
ism does  not  seem  to  be  altered.  The  blood-pressure  is  often  increased 
at  first,  but  soon  falls  after  large  doses.  The  cause  of  this  fall  has 
been  a  matter  of  dispute,  but  the  most  recent  investigator  (Pistorius) 
attempts  .to  bring  the  results  of  his  predecessors  into  accord  by  ex- 
plaining that  the  vaso-motor  centre  and  later  the  splanchnic  nerves  lose 
their  control  over  the  vessels.  When  the  pressure  begins  to  fall,  it 
39 


610  INORGANIC  SALTS,  ACIDS  AND  BASES. 

may  be  restored  by  stimulation  of  the  vaso-motor  centre,  but  this  loses 
its  effect  later,  although  direct  stimulation  of  the  splanchnic  nerves 
still  increases  the  tension.  Still  later  the  splanchnics  lose  their  action 
through  paralysis  of  their  ends,  or  of  the  vascular  walls,  while  the 
other  vaso-constrictor  nerves  are  still  capable  of  narrowing  the  vessels  ; 
for  instance  stimulation  of  the  cervical  sympathetic  still  causes  pallor 
of  the  ear,  so  that  this  action  of  the  drug  seems  to  be  confined  to  the 
splanchnic  area.  The  dilation  of  the  mesenteric  vessels  leads  to  very 
marked  congestion  of  the  stomach  and  bowel,  and  along  with  the  les- 
sened efficiency  of  the  heart  reduces  the  blood-pressure  to  zero.  Some 
evidence  has  been  brought  forward  that  under  arsenic  the  capillaries 
permit  the  passage  of  fluid  into  the  tissues  more  readily  than  normally  ; 
this  may  explain  the  appearance  of  oedema  in  cases  of  poisoning  and 
also  the  large  amount  of  fluid  in  the  stools  and  vomited  matter. 

The  Respiration  is  somewhat  accelerated  at  first  by  the  intravenous 
injection  of  small  quantities  of  arsenic,  but  afterwards  returns  to  its 
normal  rhythm.  In  cases  of  poisoning  in  man  the  respiration  does 
not  seem  to  be  much  affected  until  late,  but  it  ceases  before  the  heart, 
probably  from  the  exhaustion  and  low  blood-pressure,  and  not  from 
any  specific  action  on  the  centre. 

The  action  of  arsenic  on  the  Central  Nervous  System  has  been  re- 
peatedly examined.  A  descending  paralysis  is  elicited  in  the  frog,  the 
animal  first  losing  its  spontaneous  movements,  and  then  its  reflexes, 
and  the  terminations  of  the  motor  nerves  being  involved  only  very  late 
in  the  intoxication.  There  is  no  question  that  the  brain,  spinal  cord 
and  nerve  ends  are  directly  acted  on  in  these  animals,  for  paralysis  is 
elicited  by  arsenic  much  sooner  than  by  arrest  of  the  circulation  by 
excision  of  the  heart.  In  mammals  there  are  generally  no  certain  in- 
dications of  direct  action  on  the  nervous  system  in  acute  poisoning, 
for  the  weakness  and  prostration,  and  the  final  loss  of  consciousness 
and  coma  may  be  attributed  to  the  exhaustion  from  the  gastro-intes- 
tinal  effects  rather  than  to  the  centres  being  immediately  affected.  At 
the  same  time  the  acceleration  of  the  respiration  in  the  beginning  of 
the  intoxication,  and  the  paralysis  of  the  vaso-rnotor  centres,  would 
seem  to  point  to  a  direct  action  on  the  medulla  oblongata. 

The  pathology  of  the  nervous  disturbances  observed  in  chronic  poi- 
soning, and  often  after  a  single  large  but  not  immediately  fatal  dose,  is 
still  obscure,  and  probably  bears  no  relation  to  the  symptoms  observed 
in  animals  in  acute  poisoning.  In  many  cases  of  paralysis,  there  is 
distinct  tenderness  along  the  course  of  the  nerve  trunks,  which  would 
suggest  peripheral  neuritis  as  the  cause.  Kreyssig  could  find  no  altera- 
tions in  the  spinal  cord  in  cases  of  poisoning  in  animals  except  occa- 
sional haemorrhages,  which  did  not  seem  to  be  of  consequence.  Jaschke 
and  Alexander  observed  peripheral  neuritis  in  animals,  and  the  ques- 
tion therefore  seemed  decided  in  favor  of  the  peripheral  origin  of  the 
symptoms.  More  recently,  however,  in  two  autopsies  of  persons  suffer- 
ing from  arsenical  paralysis,  undoubted  lesions  of  the  spinal  cord  have 
been  described.  The  symptoms  point  so  unmistakably  to  peripheral 


ARSENIC.  611 

neuritis  as  the  cause,  however,  that  the  almost  universal  opinion  is 
that  the  nerve  fibres  are  the  primary  point  of  attack,  although  in 
severe  cases  the  affection  may  involve  the  nerve  cells  in  the  cord  in 
addition. 

The  peripheral  nerves  and  the  muscles  are  little  affected  by  arsenic  in 
acute  poisoning  ;  but  the  muscles  of  a  frog  poisoned  with  arsenic  are  found 
to  lose  their  irritability  somewhat  sooner  than  those  of  one  whose  circulation 
and  central  nervous  system  have  been  destroyed,  so  that  the  poison  has  some 
deleterious  effect  on  them  also. 

The  unbroken  Skin  is  not  affected  by  arsenic,  unless  when  it  is  ap- 
plied repeatedly  or  allowed  to  remain  in  contact  with  it  for  some  time, 
when  it  may  give  rise  to  redness,  pustules  or  vesicles  and  later  to 
violent  erysipelatoid  inflammation.  It  has  not,  however,  any  such 
corrosive  action  on  the  skin  as  is  possessed  by  strong  acids,  and 
the  subcutaneous  injection  of  arsenic  is  not  painful.  It  is  more 
active  when  applied  to  denuded  surfaces  and  to  the  mucous  mem- 
branes, destroying  them  to  some  depth  and  causing  acute  pain,  but 
even  here  it  acts  more  slowly  than  ordinary  caustics.  It  seems  to  act 
only  upon  living  cells,  and  unlike  acids  and  alkalies,  forms  no  combi- 
nations with  the  dead  tissues.  The  local  effects  of  arsenic  on  the  skin 
are  seen  only  in  workmen  handling  arsenic,  as  in  color  factories,  in 
which  affections  of  the  skin  of  the  face,  hands  and  scrotum  are  by  no 
means  rare. 

In  arsenic  poisoning  skin  eruptions  are  common,  and  may  be  due  in 
part  to  circulatory  disorders,  but  are  to  be  ascribed  for  the  most  part 
to  the  direct  action  of  the  drug  on  the  skin.  This  appears  to  acceler- 
ate the  growth  and  proliferation  of  the  epithelium,  which  is  found  to 
be  increased  in  thickness,  but  which  in  very  severe  cases  shows  signs 
of  atrophy  and  degeneration.  Arsenic  has  been  found  in  ap- 
preciable amount  in  the  hair,  epidermal  scales,  and  in  the  fluid  of 
a  blister  in  patients  treated  with  it,  and  changes  in  the  condition  of 
the  skin  in  animals  have  also  been  observed.  Thus  Ringer  found  the 
epidermis  of  the  frog  peel  off  with  great  ease  when  it  was  poisoned 
with  arsenic,  and  Nunn  ascribes  this  to  the  softening  of  the  protoplasm 
of  the  deeper  cells  of  the  epidermis  ;  analogous  changes  have  been  ob- 
served in  the  cornea. 

The  melanosis  of  arsenic  poisoning  seems  to  be  due  to  the  deposi- 
tion not  of  an  arsenical  compound,  but  of  some  organic  product  in  the 
deeper  layers  of  the  corium.  The  symptoms  of  irritation  of  the  mu- 
cous membranes  of  the  eye,  nose  and  larynx  are  analogous  to  the  skin 
eruptions. 

The  action  of  arsenic  on  The  Blood  is  still  obscure,  although  it  is  fre- 
quently prescribed  in  various  forms  of  anemia.  In  chlorosis  and  in 
normal  persons,  it  is  said  to  diminish  the  number  of  the  red  corpuscles, 
but  not  to  alter  the  total  hemoglobin  of  "the  blood.  In  a  case  of 
pernicious  anaemia  recently  examined  by  Engel,  it  was  found  that  ar- 


612  INORGANIC  SALTS,   ACIDS  AND  BASES. 

senic  increased  the  number  of  young  newly  formed  red  cells  while  the 
number  of  more  mature  corpuscles  was  diminished.  Bettmann  states 
that  in  subacute  poisoning  in  rabbits,  the  red  cells  and  hsemoglobin  are 
diminished,  and  nucleated  red  cells  appear  in  the  blood  in  some  num- 
ber ;  he  holds  that  arsenic  acts  on  the  blood,  and  also  on  the  blood- 
forming  organs.  Stockman  and  Greig  found  the  blood  cells  and 
haemoglobin  unaltered  by  arsenic  in  normal  animals,  but  describe  the 
bone-marrow  as  evidently  in  a  state  of  unusual  activity,  indicated  by 
its  increased  vascularity,  greater  number  of  red  blood  corpuscles  and 
lessened  fat  cells. 

In  some  cases  of  arsenic  poisoning  Fever  is  observed ;  this  does  not 
seem  due  to  any  specific  action  of  the  drug  but  to  the  inflammation  of 
the  mucous  membranes  and  the  skin. 

The  Metabolism  is  affected  by  a  poisonous  dose  of  arsenic  in  the 
same  way  as  by  phosphorus,  but  the  alteration  is  not  generally  so 
marked  and  is  liable  to  be  overlooked,  owing  to  the  more  intense  action 
on  the  alimentary  canal.  The  nitrogen  of  the  urine  is  considerably 
greater  than  that  of  inanition,  but  it  is  not  quite  clear  whether  this 
is  due  to  an  increase  in  the  urea  or  to  other  nitrogenous  substances. 
The  ammonia  is  probably  augmented,  for  a  considerable  amount  of 
lactic  acid  has  been  obtained  from  the  urine,  and  the  alkalinity  of  the 
blood  is  reduced  owing  to  the  formation  of  this  acid  in  excess.  The 
glycogen  of  the  liver  disappears  entirely,  and  the  liver  seems  incapable 
of  forming  it  from  the  sugar  of  the  food.  Lesion  of  the  medulla 
oblongata  (diabetes  puncture)  does  not  cause  glycosuria  after  arsenic, 
but  curara  and  other  drugs  are  still  capable  of  eliciting  this  symptom. 
The  fatty  degeneration  of  the  epithelium  of  the  stomach  and  intestine 
has  been  mentioned  already,  but  this  alteration  is  not  confined  to  these 
tissues,  being  found  in  the  liver  and  kidney,  in  the  muscle  cells  of  the 
heart,  blood  vessels  and  striated  muscles,  and  in  the  lining  epithelium 
of  the  alveoli  of  the  lungs.  Small  necrotic  foci  have  been  observed 
by  Wolkow  in  the  liver,  along  with  signs  of  active  division  of  the 
parenchymatous  cells,  as  in  phosphorus  poisoning. 

Many  of  these  changes  admit  of  the  same  explanation  as  that  given 
in  phosphorus  poisoning,  namely,  that  arsenic  lessens  the  oxidation  of 
the  tissues  and  causes  fatty  degeneration  of  the  cells  of  various  organs  ; 
it  may  also  increase  the  waste  of  the  proteids  of  the  body  directly, 
but  the  increase  in  the  nitrogen  of  the  urine  may  perhaps  be  sec- 
ondary to  the  other  features.  Attempts  have  been  made  to  demonstrate 
the  lessened  oxidation  by  estimating  the  respiratory  gases,  but  here, 
as  in  phosphorus,  no  satisfactory  results  can  be  obtained  by  this  method, 
owing  to  the  slow  progress  of  the  intoxication,  and  to  the  diminished 
movement  and  retarded  digestion  ;  these  in  themselves  are  sufficient  to 
cause  a  marked  fall  in  the  output  of  carbonic  acid  and  in  the  absorp- 
tion of  oxygen,  without  any  direct  action  on  the  tissue  cells.  The 
metabolism  is  less  affected  by  arsenic  than  by  phosphorus,  however, 
for  the  fatty  degeneration  is  less  marked  and  less  lactic  acid  is  ex- 
creted. Nencki  and  Sieber  have  also  shown  that  benzol  can  be  oxi- 


ARSENIC.  613 

dized  to  phenol  in  animals  poisoned  with  arsenic,  while  in  phosphorus 
poisoning  the  tissues  are  unable  to  effect  this. 

The  fatty  degeneration  may  have  the  same  results  as  in  phosphorus 
poisoning.  The  liver  is  somewhat  enlarged  and  the  pressure  on  the 
bile  ducts  prevents  the  escape  of  bile  into  the  intestine,  and  thus 
induces  jaundice  and  the  appearance  of  bile  pigments  and  bile  acid  in 
the  urine.  Jaundice  is  seldom,  however,  a  very  marked  feature  in 
arsenic  poisoning,  and  is  often  entirely  absent.  The  bile  is  said  to  con- 
tain albumin,  red  blood  cells,  and  casts  as  in  phosphorus  poisoning,  but 
does  not  present  other  changes  except  immediately  before  death 
(Pilzecker). 

The  prolonged  administration  of  arsenic  in  quantities  insufficient  to 
produce  chronic  poisoning  is  reputed  to  have  some  effect  on  the 
Growth  and  Nutrition.  It  is  difficult  to  obtain  accurate  data  in  regard 
to  this  point,  and  while  the  improvement  in  nutrition  is  attested  by  a 
number  of  independent  observers,  other  equally  careful  investigators 
have  not  been  able  to  confirm  their  results.  Gies  treated  some  of  a 
litter  of  young  rabbits  with  arsenic  in  minute  doses  for  several  weeks, 
and  found  that  they  weighed  more,  and  were  larger  in  every  way  than 
the  untreated  animals  ;  the  subcutaneous  fat  was  much  greater  in 
amount,  the  bones  were  longer,  and  the  muscles  more  developed.  The 
long  bones  presented  the  appearance  described  by  Wegner  under  phos- 
phorus treatment,  being  longer  and  containing  more  dense  bone  both 
in  the  shaft  and  the  epiphyses.  Female  rabbits  treated  with  arsenic 
bore  young  of  abnormal  size  and  weight ;  Gies,  in  fact,  supposes  that 
their  size  caused  difficulties  in  their  passage  through  the  pelvis,  for 
they  were  all  born  dead.  Several  other  observers  have  described  a 
more  rapid  growth  and  greater  activity  in  young  animals  treated  with 
arsenic,  and  an  increase  in  weight  is  often  noted  in  man.  On  the 
other  hand  Stockman  and  Greig  observed  no  change  in  the  growth  of 
animals  under  prolonged  treatment  with  arsenic,  and  found  that  the  only 
tissues  affected  were  the  growing  bones,  which  appeared  denser  than  usual. 

The  improvement  in  nutrition  has  not  been  explained,  though  a  slight 
decrease  in  the  nitrogenous  excretion  and  in  the  amount  of  nitrogen 
in  the  stools  has  been  noted  by  Weiske,  who  holds  that  more  of  the 
food  is  utilized  by  the  digestive  apparatus,  and  at  the  same  time,  less 
proteid  is  decomposed  in  the  tissues.  The  change  in  the  amount  of 
nitrogen  excreted  is  so  small,  however,  that  doubt  may  be  entertained 
whether  it  may  not  be  due  to  unavoidable  errors  in  the  estimation,  and 
other  investigators  have  been  unable  to  detect  any  alteration  attribut- 
able to  the  drug.  Fresh  investigation  of  this  point  is  thus  required 
before  certainty  can  be  reached  regarding  the  effects  on  the  nutrition, 
and  still  more  regarding  the  explanation  of  the  alterations. 

When  small  quantities  of  arsenic  are  taken  habitually,  Tolerance  is 
established,  and  the  dose  may  be  gradually  increased  until  it  far  ex- 
ceeds that  which  would  be  poisonous  in  ordinary  persons.  This  is 
the  explanation  of  arsenic-eating  which  is  known  to  exist  in  different 
parts  of  the  world,  but  which  is  most  widespread  and  best  known  in 


614  INORGANIC  SALTS,  ACIDS  AND  BASES. 

Styria  and  the  Tyrol.  The  peasants  there  indulge  in  the  poison  habit- 
ualty,  and  believe  that  it  enables  them  to  work  better,  and  in  particular 
to  climb  the  mountains  with  less  effort  and  less  respiratory  distress. 
They  also  credit  it  with  improving  their  complexions  and  general  ap- 
pearance, and  give  it  to  their  horses  in  order  to  render  their  coats  more 
smooth  and  glossy,  and  to  make  them  stronger  and  fatter.  Doubt  was 
formerly  entertained  as  to  the  truth  of  the  statements  made  regarding 
the  doses  used  by  these  people,  but  this  was  definitely  settled  by  Knapp, 
who  administered  0.4  G.  (7  grs.)  of  arsenious  acid  to  one  of  the  peas- 
ants at  Graz  without  inducing  any  effects  whatsoever.  Large  quanti- 
ties of  arsenic  have  also  been  isolated  from  the  urine  of  arsenic  eaters, 
showing  that  much  of  the  drug  is  absorbed.  Arsenic-eating  is  said  to 
be  indulged  in  to  a  considerable  extent  by  young  women  in  some  coun- 
tries with  the  object  of  improving  the  complexion  and  figure,  and  cases 
of  arsenic  habit  have  been  described  in  different  parts  of  America  and 
elsewhere.  As  far  as  can  be  observed  the  habit  is  not  deleterious,  for 
the  Styrian  peasants  live  to  old  age,  and  no  symptoms  attributable  to 
the  poison  have  been  noted.  As  a  general  rule  large  doses  are  taken 
once  or  twice  a  week,  and  no  fluid  is  swallowed  for  some  time  after- 
wards, so  that  some  of  the  poison  may  pass  through  the  bowel  unab- 
sorbed.  No  tolerance  for  arsenic  has  been  established  in  animals,  even 
by  prolonged  treatment  with  minute  doses. 

As  a  contrast  to  the  Styrian  peasants,  the  miners  of  Reichenstein 
may  be  mentioned,  who  are  constantly  exposed  to  arsenic  owing  to  its 
being  contained  in  large  quantities  in  the  ore.  These  people  are  de- 
scribed by  Geyer  as  shortlived,  very  subject  in  childhood  to  severe 
rickets  and  in  adult  life  to  dropsies  and  respiratory  diseases ;  they 
offer  little  resistance  to  microbial  infection  and  frequently  present  the 
skin  and  nervous  symptoms  of  arsenic  poisoning.  Why  arsenic  should 
be  beneficial  or  at  any  rate  harmless  at  Graz,  and  so  deleterious  in 
Reichenstein,  it  is  impossible  to  state  at  present.  But  it  is  not  unlikely 
that  the  contrast  may  rest  upon  differences  in  the  general  nutrition,  for 
Delepine  and  others  have  found  that  animals  supplied  with  abundant 
food  and  in  good  hygienic  conditions  survive  under  chronic  arsenic 
poisoning  much  longer  than  less  well  nourished  ones.  This  difference 
in  the  nutrition  may  also  explain  the  fact  that  in  epidemic  poisoning, 
as  in  the  Manchester  cases,  comparatively  few  of  the  persons  exposed 
to  the  poison  exhibited  any  symptoms  from  it. 

Arsenic  is  Excreted  for  the  most  part  in  the  urine,  to  a  much  smaller 
extent  in  the  stomach  and  bowel  and  along  the  respiratory  mucous 
membranes.  Traces  are  eliminated  in  the  skin  secretions,  in  the  hair, 
and  in  the  milk,  and  fatal  intoxication  has  been  observed  in  a  child 
from  the  milk  of  its  mother,  who  was  suffering  from  acute  poisoning. 
In  the  urine  arsenic  appears  in  part  in  organic  combinations,  in  part, 
according  to  Selmi,  in  the  form  of  a  volatile  organic  base,  which  is  in- 
tensely poisonous  and  causes  convulsions  in  frogs.  Arsenic  is  only 
slowly  excreted ;  it  is  stated  to  have  been  detected  in  the  urine  2-3 
months  after  its  administration,  but  it  has  been  shown  to  occur  in  the 


ARSENIC.  615 

urine  of  a  number  of  persons  who  presented  no  signs  of  poisoning  and 
had  not  been  treated  with  arsenic,  so  that  it  is  possible  that  in  those 
cases  of  slow  elimination  the  arsenic  of  the  urine  did  not  arise  from  the 
single  administration,  but  from  its  subsequent  absorption  from  some 
other  source,  such  as  the  water  or  air.  There  is  no  question,  however, 
that  it  remains  in  the  system  longer  than  many  other  poisons.  It  is 
probable  that  the  effects,  especially  the  paralysis,  last  long  after  the 
drug  has  been  excreted,  lesions  having  been  induced  which  are  only 
slowly  recovered  from. 

Arsenic  is  found  in  largest  quantity  in  the  liver,  in  which  it  forms 
a  firm  combination  with  the  nucleins  ;  it  is  also  deposited  in  the  kid- 
ney, in  the  walls  of  the  stomach  and  intestine,  and  in  the  spleen  and 
lungs.  Much  smaller  quantities  are  found  in  the  muscles  and  in  the 
nervous  tissues,  which  were  formerly  supposed  to  contain  more  than 
the  liver.  It  is  stated  that  in  cases  of  poisoning  arsenic  is  found  in 
the  white  matter  of  the  brain  in  much  larger  proportion  than  in  the 
cortex.  In  the  blood  most  of  the  arsenic  is  said  to  be  contained  in  the 
blood  cells,  comparatively  little  being  free  in  the  plasma.  Arsenic  has 
been  detected  in  the  cancellous  bones  of  the  skull  and  vetebrse,  after  it 
had  disappeared  from  all  the  other  organs. 

Arsenic  is  poisonous  to  many  of  the  lower  forms  of  life,  as  well  as  to  the 
vertebrates  ;  thus  it  has  been  found  that  its  presence  in  comparatively  dilute 
solution  (one  part  of  arsenious  acid  in  30,000  parts  of  water)  hinders  the 
development  of,  and  eventually  kills  alga3  and  the  seeds  of  the  higher  plants. 
On  the  other  hand,  moulds  grow  abundantly  in  a  solution  of  arsenite  of 
potash  (1  per  cent.)  containing  some  organic  matter,  and  the  alcoholic  fer- 
mentation proceeds  in  the  presence  of  arsenic,  although  it  is  somewhat  re- 
tarded at  first ;  very  dilute  solutions  of  arsenic  even  accelerate  the  fermen- 
tation, as  is  true  of  most  other  antiseptics.  Arsenious  acid  is  only  about 
one-tenth  as  strong  an  antiseptic  as  perchloride  of  mercury,  and  the  spores 
of  anthrax  are  destroyed  only  after  ten  days  in  a  one  per  mille  solution.  It 
has  therefore  a  greater  antiseptic  power,  than  many  of  the  other  acids,  but 
compared  with  its  action  on  the  higher  forms  of  life,  it  is  but  slightly 
poisonous  to  the  fungi.  It  seems  to  have  no  effect  on  the  activity  of  the 
ferments,  such  as  pepsin,  myrosin  and  emulsin. 

The  arsenates  are  much  less  harmful  to  lowly  organized  forms,  for  seeds 
and  algae  as  well  as  moulds  grow  in  a  neutral  solution  abundantly,  and  even 
the  infusoria  do  not  seem  injured  by  it  to  any  marked  degree.  Apparently 
these  plants  and  animals  are  incapable  of  reducing  it  to  arsenious  acid,  and 
are  therefore  not  more  affected  by  it  than  by  other  acids. 

The  bodies  of  persons  poisoned  with  arsenic  are  said  to  remain  undecom- 
posed  for  a  remarkably  long  time,  and  to  tend  to  become  mummified.  The 
statement  is  still  disputed,  but  is  vouched  for  by  a  number  of  authorities. 
It  is  certainly  not  invariably  the  case,  and  little  weight  is  to  be  laid  upon 
mummification  in  determining  whether  arsenic  poisoning  was  the  cause  of 
death  in  exhumed  persons. 

No  account  of  the  pharmacology  of  arsenic  would  be  complete  without 
mention  of  the  theory  advanced  by  Binz  and  Schulz  to  explain  its  action. 
They  suppose  that  arsenious  acid  is  oxidized  to  arsenic  acid  by  the  living  tis- 
sues, and  the  arsenic  acid  again  reduced  to  arsenious.  In  this  way  oxygen  is 
alternately  withdrawn  from,  and  supplied  to  the  protoplasm,  and  this  alter- 
nate reduction  and  oxidation  they  suppose  to  be  the  essential  feature  of  the 
action  of  arsenic.  The  grounds  on  which  this  explanation  is  based  must  be 
sought  in  the  numerous  papers  on  the  subject  by  these  authors,  and  it  may 


616  INORGANIC  SALTS,   ACIDS  AND  BASES. 

suffice  here  to  state  that  while  arsenic  acid  appears  to  be  reduced,  and 
arsenious  acid  oxidized  in  the  tissues,  these  processes  are  probably  only 
gradual.  Otherwise  it  would  be  difficult  to  explain  how  arsenious  acid  is  so 
much  more  poisonous  than  arsenic  acid,  for  if  the  latter  were  readily  re- 
duced to  arsenious  acid  it  would  be  equally  toxic. 

Arsenic  and  phosphorus  are  included  in  one  group  in  chemistry,  and 
their  effects  on  living  organisms  present  sufficient  resemblance  to  jus- 
tify their  association  in  the  pharmacological  system.  The  mucous 
membranes  and  the  skin  are  more  affected  by  arsenic,  however,  and 
the  circulation  is  more  rapidly  depressed,  while  the  fatty  degeneration 
of  the  protoplasm  of  the  vertebrates  is  much  more  prominent  in  phos- 
phorus poisoning.  ,The  differences  between  their  effects  are  more  in 
degree  than  in  kind,  and  there  seems  no  question  that  their  ultimate 
action  on  protoplasm  is  of  the  same  nature.  It  is  to  be  noted,  how- 
ever, that  there  is  no  reason  to  suppose  that  phosphorus  owes  its 
action  to  any  of  its  numerous  compounds  with  oxygen,  while  it  is 
probable  that  the  oxides  of  arsenic  alone  are  capable  of  modifying 
vital  functions. 

The  Sulphur  Compounds  of  arsenic  are  entirely  insoluble  and  are  therefore 
not  absorbed  as  such,  but  it  seems  likely  that  small  quantities  of  arsenious 
acid  are  formed  from  them  in  the  intestine  by  microbes.  Commercial  orpi- 
ment  often  contains  large  amounts  of  arsenious  acid. 

Arseniuretted  Hydrogen  (AsH3)  is  an  exceedingly  poisonous  gas,  which 
has  caused  a  number  of  fatal  accidents  from  being  inhaled  accidentally  in 
chemical  laboratories.  One  source  of  danger  is  the  liberation  of  hydrogen 
from  acids  by  the  action  of  zinc,  which  often  contains  arsenic  and  therefore 
gives  rise  to  this  gas.  It  differs  entirely  from  the  oxides  of  arsenic  in  its  ac- 
tion, and  there  is  no  reason  to  suppose  that  it  forms  these  in  the  body.  Pos- 
sibly traces  of  arseniuretted  hydrogen  are  formed  from  arsenious  acid  in  the 
intestine,  but  in  insufficient  quantities  to  have  any  appreciable  effect.  Ar- 
seniuretted hydrogen  acts  as  a  molecule,  AsH3,  arsenites  as  ions,  and  the 
fact  that  both  molecule  and  ion  contain  an  atom  of  arsenic,  does  not  neces- 
sarily entail  that  their  effects  shall  bear  any  resemblance. 

Arseniuretted  hydrogen  acts  by  destroying  the  red  corpuscles  of  the  blood, 
and  induces  intense  headache,  nausea  and  vomiting,  prostration  and  faint- 
ing fits,  cyanosis  and  collapse.  Haemoglobin,  methsemoglobin,  hasmatinand 
occasionally  blood  are  passed  in  the  urine,  and  more  rarely  the  stools  contain 
blood.  Sometimes  the  urine  is  entirely  suppressed  from  the  tubules  being 
plugged  with  blood  cells  and  debris,  and  intense  icterus  appears  from  the 
formation  of  excess  of  bile  pigment  from  the  haemoglobin  of  the  disinte- 
grated corpuscles.  (Edema  of  the  lungs  or  sudden  failure  of  the  heart  is  the 
cause  of  death.  Some  of  the  gas  is  excreted  by  the  lungs,  and  may  be  rec- 
ognized by  its  garlic  odor,  and  some  arsenic  appears  in  the  urine,  but  it  is 
not  known  in  what  form. 

PREPARATIONS. 

ARSENI  TRIOXIDUM  (TL  S.  P.),  ACIDUM  ARSENIOSUM  (B.  P.)  (As2O3), 
arsenous  or  arsenious  acid  anhydride,  white  arsenic,  ratsbane,  forms  a  white 
powder,  or  opaque,  porcelain-like  masses,  or  a  transparent,  amorphous  sur- 
face like  glass.  It  dissolves  slowly  in  cold  water,  the  glassy  variety  requir- 
ing about  thirty,  the  porcelain  about  eighty  parts  of  water.  It  is  almost 
tasteless  and  has  no  odor.  1-5  mgs.  (sV-i1*  gr.),  in  pill  or  solution,  after 
meals.  The  "Asiatic"  pill  consists  of  arsenic,  black  pepper  and  liquorice. 

Liquor  Acidi  Arsenosi  (U.  S.  P.),  Liquor  Arsenici  Hydrochloricus  (B.  P.),  a 
one  per  cent,  solution  of  arsenous  acid  acidulated  with  hydrochloric  acid. 
0.05-0.5  c.c.  (1-8  mins.),  3-5  drops  three  times  daily,  after  meals. 


ARSENIC.  617 

LIQUOR  POTASSII  ARSENITIS  (U.  S.  P.),  LIQUOR  ARSENICALIS  (B.  P.),  Fow- 
ler's solution,  contains  one  per  cent,  of  arsenous  acid  neutralized  with  bicar- 
bonate of  potash,  to  which  compound  tincture  of  lavender  is  added  to  give 
color  and  flavor.  0.05-0.5  c.c.  (1-8  mins.),  3-5  drops  three  times  daily, 
after  meals. 

Sodii  Arsenas  (U.  S.  P.)  (Na2HAsO4  +  7H2O)  forms  colorless,  odorless  crys- 
tals, very  soluble  in  water,  with  a  mild,  alkaline  taste.  1-5  mgs.  (sV-rV  gr.). 

Sodii  Arsenas  (B.  P.),  Sodii  Arsenas  Exsiccatus  (U.  S.  P.)  (Na2HAsO4),  is 
prepared  from  the  ordinary  arsenate  (U.  S.  P.)  by  driving  off  the  water  of  crys- 
tallization, and  forms  a  white  powder.  ^VrV  §r- 

Liquor  Sodii  Arsenatis  (U.  S.  P.,  B.  P.),  Pearson's  solution,  a  one  per  cent, 
solution  of  the  sodium  arsenate  of  the  respective  pharmacopoeias.  0.05-0.5 
c.c.  (1-8  mins.). 

Arseni  lodidum  (U.  S.  P.),  Arsenii  lodidum  (B.  P.)  (AsI3),  glossy,  orange- 
red  crystals  with  an  iodine  odor  and  slowly  giving  off  iodine  in  the  air  ;  it  is 
soluble  in  7  parts  of  water,  but  the  solution  soon  decomposes  into  arsenous 
and  hydriodic  acids.  3-10  mgs.  (^o-i  gr.). 

LIQUOR  ARSENI  (ARSENII,  B.  P.)  ET  HYDRARGYRI  IODIDI  (U.  S.  P.,  B.  P.), 
Donovan's  solution,  contains  one  per  cent,  of  arsenic  iodide  and  one  per 
cent,  of  red  mercuric  iodide.  This  solution  is  clear  and  yellowish,  without 
odor,  but  with  a  harsh  metallic  taste.  0.3-1.3  c.c.  (5-20  mins.),  after  meals. 

Ferri  Arsenas.     (See  Iron.) 

Some  mineral  waters  contain  arsenic,  that  of  Levico  as  much  as  8  mgs. 
per  litre. 

Therapeutic  Uses.  —  The  action  of  arsenic  as  ascertained  from  ex- 
periments on  the  lower  animals  and  from  cases  of  poisoning  in  man 
throws  little  light  on  its  use  in  therapeutics,  and  so  little  is  known  of 
the  pathology  of  most  of  the  conditions  in  which  it  is  found  of  benefit, 
that  no  attempt  can  be  made  to  bring  the  two  series  of  observations 
into  relation. 

Arsenious  acid  has  been  used  externally  as  a  caustic,  formerly  in 
various  forms  of  malignant  disease,  more  recently  in  lupus,  in  which 
it  is  said  to  destroy  the  diseased  surface  while  leaving  the  healthy  skin 
unaffected.  It  has  been  superseded,  however,  by  the  introduction  of 
surgical  measures,  such  as  scraping  with  the  sharp  spoon.  Arsenic  in 
substance  is  still  used  in  dentistry  to  destroy  the  pulp  in  decayed  teeth. 

Internally  arsenic  is  used  in  malarial  disease,  especially  in  invete- 
rate cases  in  which  there  in  much  cachexia.  In  acute  cases  it  is  also 
of  benefit,  but  is  much  less  certain  in  its  effects  than  quinine,  and  it  is 
very  questionable  whether  it  acts  on  the  malarial  organism,  for  its  effi- 
cacy often  seems  due  rather  to  its  improving  the  general  nutrition  and 
lessening  the  cachexia  and  wasting.  Many  authorities,  in  fact,  depre- 
cate the  use  of  arsenic  in  acute  malaria,  and  would  limit  its  use  to  the 
cachexia  of  old  disease,  while  others  advise  its  use  with  iron  in  ordinary 
cases,  after  the  acute  stage  has  been  successfully  treated  with  quinine. 

Arsenic  has  also  been  used  with  benefit  in  neuralgia,  especially  when 
it  assumes  a  periodic  character,  and  in  chronic  rheumatism,  but  in  many 
cases  no  definite  improvement  follows,  and  the  conditions  under  which 
it  is  of  value  cannot  be  more  accurately  defined  at  the  present  time. 
Old  cases  of  chorea  often  improve  under  arsenic,  which  may  imply 
some  action  on  the  central  nervous  system,  although,  as  has  been 
stated,  little  alteration  in  the  nervous  functions  is  observed  in  ani- 


618  INORGANIC  SALTS,  ACIDS  AND  BASES. 

mals  except  under  very  large  doses.  Asthma  has  also  been  treated 
with  arsenic  given  by  the  stomach,  or  by  the  inhalation  of  arsenic 
from  smoking  cigarettes  made  with  arsenical  paper. 

Small  doses  of  arsenic  are  often  of  service  in  increasing  the  appetite 
and  improving  the  general  condition  in  diseases  accompanied  by 
cachexia,  want  of  appetite,  general  weakness  and  apathy. 

In  pernicious  anaemia,  arsenic  is  said  to  be  beneficial,  but  the  im- 
provement is  only  temporary.  Many  forms  of  skin  disease  are  treated 
with  arsenic,  some  of  them  with  the  happiest  results.  Thus  in  psoria- 
sis, chronic  eczema  and  lichen  ruber,  marked  improvement  or  complete 
recovery  often  dates  from  the  beginning  of  the  arsenic  treatment.  It 
is  generally  advised  only  in  the  chronic  forms,  and  is  said  to  be  posi- 
tively deleterious  during  the  earlier  stages  of  rapid  cell  proliferation. 

In  lymphoma,  arsenic  has  been  given  internally  and  also  by  direct 
injection  into  the  tumors,  and  often,  though  not  by  any  means  inva- 
riably, proves  of  value.  Various  other  forms  of  leucaemia  have  been 
treated  with  less  success. 

The  action  of  arsenic  in  reducing  the  glycogen  of  the  liver  suggested 
its  use  in  diabetes,  but  most  reliable  authorities  have  failed  to  obtain 
satisfactory  results.  Arsenic  has  been  used  in  some  forms  of  trypano- 
soma  infection  in  animals,  and  has  been  found  to  improve  similar  con- 
ditions in  man. 

Arsenic  is  in  the  great  majority  of  cases  prescribed  in  the  form  of 
Fowler's  solution.  It  is  generally  advisable  to  commence  with  small 
doses,  and  to  increase  them  as  tolerance  is  developed,  but  some  au- 
thorities advise  large  doses  from  the  outset.  Arsenic  is  always  pre- 
scribed to  be  taken  after  meals,  in  order  to  avoid  any  possible  action 
on  the  digestion.1  Several  authors  have  recommended  the  hypodermic 
injection  of  Fowler's  solution  diluted  with  two  parts  of  water.  (Dose 
0.5  c.c.,  8  mins.)  Arsenic  is  contraindicated  in  cases  of  irritation  of 
the  stomach  and  bowel,  and  is  generally  avoided  during  acute  fever, 
except  in  malaria. 

If  symptoms  of  chronic  poisoning  begin  to  assert  themselves,  the 
drug  must  be  discontinued  at  once.  The  first  symptoms  are  generally 
disordered  digestion,  loss  of  appetite  and  discomfort  in  the  stomach 
region,  a  feeling  of  constriction  in  the  throat  and  redness  and  swelling 
of  the  conjunctiva  and  eyelids. 

In  Acute  Arsenic  Poisoning  the  stomach  ought  to  be  emptied  at  once 
by  means  of  the  stomach  tube  or  by  an  emetic  (apomorphine).  The 
stomach  washing  is  to  be  continued  for  some  time,  as  arsenic  is  very 
insoluble.  Iron  or  magnesium  preparations  have  been  advised  in  order 
to  form  a  loose  chemical  combination  with  the  arsenic ;  freshly  pre-r 
cipitated  iron  hydrate  formed  by  adding  magnesia  to  a  solution  of  iron 
sulphate  forms  the  well-known  arsenic  antidote,  or  magnesia  alone  is 
sometimes  given  shaken  up  with  water.  Experiments  on  animals 

1  Cacodylate  of  sodium,  in  doses  of  0.05  G.  (1  gr. ),  has  recently  been  recom- 
mended as  a  substitute  for  the  ordinary  arsenical  preparations.  It  appears  to  be  ex- 
creted for  the  most  part  unchanged  but  a  small  percentage  is  reduced  and  this  has 
the  same  effect  as  the  more  commonly  used  preparation  (Heftier). 


ARSENIC.  619 

show  these  antidotes  are  useless  and  that  reliance  is  to  be  placed  on 
repeated  and  copious  lavage  only. 

The  collapse  is  treated  by  the  ordinary  measures,  warmth  and  stimu- 
lants, such  as  caffeine  and  digitalis.  In  chronic  poisoning,  the  paraly- 
sis is  treated  by  stimulating  the  muscles  with  the  galvanic  current,  the 
other  symptoms  by  suitable  general  treatment. 

BIBLIOGRAPHY. 

A  very  complete  account  of  the  action  of  arsenic  is  given  by  Wertheimer  in  Richet's 
Dictionnaire  de  Physiologic,  i.,  p.  674.  Among  the  numberless  papers  on  Arsenic  the 
following  may  be  mentioned  : 

Boehm  u.   Unterberger.     Arch.  f.  exp.  Path.  u.  Pharm.,  ii.,  p.  89. 

Pistorius.     Ibid.,  xvi.,  p.  188. 

Kossel.     Ibid.,  y.,  p.  128. 

Gies.     Ibid.,  viii.,  p.  175. 

Saikowsky.     Virchow's  Arch.,  xxxiv.,  p.  73. 

Falck.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii.,  p.  394. 

Meyer.     Ibid.,  xiv.,  p.  329. 

Filehne.     Virchow's  Arch.,  Ixxxiii.,  p.  1. 

Schulz  u.  Binz.  Arch.  f.  exp.  Path.  u.  Pharm.,  xi.,  p_p.  131,  200  ;  xiii.,  p.  256  , 
xiv.,  p.  345;  xv.,  p.  322  ;  xxxvi.,  p.  275;  xxxviii.,  p.  259  ;  xli.,  p.  179. 

Husemann.     Deutsch.   med.  Wpch.,  1892,  p.  1081. 

Lesser.     Virchow's  Arch.,  Ixxiii.  and  Ixxiv. 

Heffter.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxi.,  p.  257. 

Heinz.     Virchow's  Arch.,  cxxvi.,  p.  495. 

Wolkow.     Ibid.,  cxxvii.,  p.  477. 

S.netana.     Wien.  klin.  VVoch.,  1897,  p.  903. 

Engel.     Virchow's  Arch.,  cxxxv.,  p.  369. 

Selmi.     Virchow-Hirsch.  Jahsresber.,  1881,  i.,  p.  413. 

Tmbert-Gourbeyre.      Des  suites  de  1'empoisonnement  arsenical.     Paris,  1881. 

Brouardel  et  Pouchet.     Bull,  de  1'acad.  de  med.,  1889,  p.  915. 

Dana.     Brain,  ix.,  p.  456. 

DaCosta.     Phila.  Med.  Times,  1881,  p.  385. 

Krehl     Deutsch.  Arch.  f.  klin.  Med.,  xliv.,  p.  325. 

Kreyssig.     Virchow's  Arch.,  cii.,  p.  286. 

Huber.     Ztschr.  f.  klin.  Med.,  xiv.,  p.  444. 

Alexander.     Habilitation-Thesis,  Breslau,  1889. 

Erlicki  u.  Rybalkin.     Arch.  f.  Psychiatrie,  xxiii.,  p.  861. 

Busscher.     Arch,  internat.  de  Pharmacodyn.,  x.,  p.  415. 

Ringer  and  Murrell.     Journ.  of  Physiol.,  i.,  p.  213. 

Nunn.     Ibid.,  i.,  p.  247. 

Putnam.     Boston  Medical  and  Surgical  Journ,  cxx.,  p.  235. 

Bettmann.     Ziegler's  Beitnige,  xxiii.,  p.  377. 

Loew.     Pfliiger's  Arch.,  xl.,  p.  444. 

Stockman  and  Greig.     Journ.  of  Physiol.,  xxiii.,  p.  376.     Journ.  of  Pathology,  1903. 

Geyer.     Arch.  f.  Dermat.  u.  Syph.,  xliii.,  p.  221. 

Reynolds  and  others.     Lancet  and  British  Med.  Journal,  1900,  ii.,  and  1901,  i.  and  ii. 

Morishima.     Arch,  internat.  de  Pharmacodyn.,  vii.,  p.  65. 

Heffter.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlvi.,  p.  230.     (Cacodylates.) 

Report  of  the  Koyal  Commission  on  Arsenical  poisoning,  1903. 

On  arseniuretted  hydrogen. 

Staddmann.     Arch.  f.  exp.  Path.  u.  Pharm.,  xvi.,  p.  221. 

Minkowski  u.  Naunyn.     Ibid.,  xxi.,  p.  14. 

Waechter.     Vierteljahr.  f.  gericht.  Med.,  xxviii.,  p.  251. 


PART  IV. 

THE   HEAVY   METALS. 
HEAVY  METALS. 

A  LARGE  number  of  important  drugs,  belonging  to  the  chemical 
series  of  heavy  nietals  resemble  each  other  so  closely  in  their  action  in 
living  organisms  that  they  may  be  readily  grouped  together  in  a  divi- 
sion of  the  pharmacological  system.  Some  authors  include  in  this 
series  arsenic  and  antimony,  but  the  former  presents  so  many  analogies 
to  phosphorus  in  its  eifects  that  it  is  preferable  to  treat  it  apart  from 
the  heavy  metals.  Antimony  is  certainly  as  closely  related  to  arsenic 
as  to  this  group,  and  may  be  regarded  as  a  connecting  link  between 
them. 

The  metals  as  such  do  not  induce  any  symptoms  except  from  their 
mechanical  properties.  Thus  mercury  may  be  swallowed  in  large 
quantities  without  causing  mercurial  poisoning,  and  silver  or  copper 
coins  are  equally  devoid  of  effect  as  poisons.  They  are  active  only 
when  they  are  capable  of  dissociation  into  ions  of  the  metal  or  of  an 
oxide.  Thus  potassium  ferrocyanide  does  not  cause  any  symptoms  of 
iron  poisoning  when  it  is  injected  into  a  vein,  because  the  iron  passes 
through  the  body  undissociated,  and  any  eifects  are  due  to  the  ferrocya- 
nide ion  and  not  to  the  iron.  In  the  same  way  compounds  of  the  metals 
with  ethyl  and  methyl,  such  as  lead  triethyl,  have  an  action  quite  dif- 
ferent from  that  of  lead,  as  long  as  they  remain  undecomposed  in  the 
tissues,  but  eventually  induce  metallic  poisoning,  as  they  are  broken 
up  into  bodies  from  which  the  lead  or  lead  oxide  ion  can  be  dissociated. 

The  action  of  the  heavy  metals  consists  of  two  parts,  the  local  effects 
induced  at  the  point  of  application,  and  the  general  effects  which  fol- 
low the  absorption  of  the  poison  into  the  blood  and  tissues.  Either  of 
these  may  be  produced  alone  by  suitable  preparations  and  modes  of 
administration,  and  they  are  to  be  regarded  as  entirely  independent  of 
each  other. 

The  Local  Action  of  the  heavy  metal  series  is  due  to  the  formation 
of  proteid  combinations.  When  the  salt  of  a  heavy  metal  is  added  to 
a  solution  of  egg  albumin,  or  of  similar  proteid,  a  precipitate  is  at 
once  formed  of  metallic  albuminate.  The  proteids  apparently  play  the 
role  of  acids,  forming  insoluble  salts  with  the  metals,  but  these  salts 
are  not  generally  of  definite  chemical  composition,  for  the  percentage 
of  metal  contained  in  the  albuminate  usually  varies  within  wide 
limits ;  in  some  cases,  however,  definite  compounds  have  been  formed. 

621 


622  THE  HEAVY  METALS. 

The  albumin  displaces  the  original  acid  of  the  salt,  which  may  be 
entirely  removed  by  prolonged  washing.  The  albuminates  of  the 
metals  are  insoluble  in  water,  but  most  of  them  are  soluble  in  excess 
of  proteid  or  of  the  metallic  solution,  and  many  of  them  may  be 
dissolved  in  solutions  of  neutral  salts  such  as  chloride  of  sodium.  In 
the  albuminates  formed  by  the  addition  of  salts  to  proteid  solutions,  the 
metals  are  combined  in  the  same  way  as  in  inorganic  salts,  and  may  be 
detected  by  their  usual  reactions.  Thus  iron  albuminate  is  rapidly 
blackened  by  the  presence  of  ammonium  sulphide,  because  ferrous  sul- 
phide is  formed  from  it  exactly  as  from  any  of  the  inorganic  salts.  On 
subjecting  these  albuminates  to  certain  chemical  manipulations,  how- 
ever, the  metal  seems  to  become  more  firmly  attached  to  the  proteid, 
for  ammonium  sulphide  acts  on  it  much  more  slowly.  The  metal  is 
then  said  to  be  masked,  because  its  presence  is  not  so  readily  detected 
as  in  ordinary  combinations.  Partially  masked  preparations  have  been 
formed  artificially,  but  in  the  body  the  process  is  carried  much  further, 
for  in  many  of  their  proteid  compounds  the  metals  cannot  be  detected 
by  any  of  the  ordinary  tests,  however  long  the  reagents  may  remain 
in  contact  with  them,  and  their  presence  is  recognized  only  when  the 
proteid  is  destroyed  by  heat  or  other  similar  agencies. 

When  a  solution  of  a  metallic  salt  comes  in  contact  with  a  living 
tissue,  such  as  the  mucous  membrane  of  the  mouth  or  stomach,  the  al- 
buminate is  at  once  formed,  and  the  acid  with  which  the  metal  was 
combined  is  set  free.  The  more  completely  dissociated  the  ions  of  the 
salt  are,  the  more  rapid  is  the  reaction  with  proteid  and  the  more  in- 
tense the  local  action.  Thus  the  more  readily  ionized  inorganic  salts 
act  more  strongly  than  the  organic  ones  which  are  slowly  dissociated, 
and  these  in  turn  are  more  liable  to  cause  marked  local  changes  than 
the  double  salts,  which  are  dissociated  with  difficulty.1  Other  factors 
determining  the  nature  of  the  local  action  are  the  character  of  the  pre- 
cipitate and  the  activity  of  the  acid  formed,  the  latter  again  varying 
with  the  extent  to  which  it  is  dissociated  into  ions ;  it  therefore  exer- 
cises the  same  astringent  or  corrosive  effects  as  if  it  had  been  applied 
uncombined,  but  its  action  may  be  modified  by  the  presence  of  a  layer 
of  metallic  albuminate  protecting  the  surface.  Thus  when  a  weak  solu- 
tion of  lead  acetate  is  applied  to  a  mucous  membrane,  the  metal  forms 
an  albuminate  with  the  proteids  lying  on  the  surface  and  in  the  more 
superficial  parts  of  the  cells.  This  albuminate  forms  a  continuous  sheet 
over  the  mucous  membrane,  and  the  very  dilute  acetic  acid  formed  is 
incapable  of  inducing  any  reaction.  If  a  stronger  solution  be  applied, 
however,  the  metallic  precipitate  extends  more  deeply  into  the  cell, 
while  the  acetic  acid,  being  more  concentrated,  exercises  some  irritant 
action.  As  the  concentration  increases,  the  deeper  parts  of  the  epi- 
thelial cells  are  coagulated,  and  at  the  same  time  the  acid  becomes  more 
destructive,  so  that  eventually  the  superficial  layer  of  the  epithelium  is 
killed  and  the  deeper  layers  are  attacked.  The  acetate  of  lead  may 
thus  act  as  an  astringent,  covering  a  mucous  surface  with  a  protective 
1  Paul.  Bedeutung  der  lonentheorie  f.  d.  physiol.  Chemie,  1901, 


THE  HEAVY  METALS.  623 

pellicle  of  insoluble  albuminate,  as  an  irritant,  which  induces  an  in- 
crease in  the  circulation  of  the  part,  a  more  rapid  division  of  the  cells 
and  an  effusion  of  liquid,  or  as  a  corrosive,  involving  the  superficial 
layer  of  cells,  and  sometimes  even  the  deeper  ones  in  its  destructive 
effects. 

When  the  nitrate  of  lead  is  applied,  the  astringent  effect  is  much  less 
evident,  the  irritant  and  corrosive  more  marked,  because  the  salt  is 
more  readily  dissociated  and  the  reaction  is  therefore  more  rapid,  and  in 
addition  the  nitric  acid  is  much  more  corrosive  than  acetic  acid.  The 
same  metal  attached  to  different  acids  may  therefore  induce  very  dif- 
ferent effects,  in  the  one  case  acting  chiefly  as  an  astringent,  in  the 
other  as  an  irritant  and  corrosive. 

The  character  of  the  precipitate  formed  also  determines  to  some  ex- 
tent the  local  action  of  the  metallic  salts.  Thus  the  salts  of  mercury 
are  more  irritant  and  corrosive  than  those  of  the  other  metals,  partly 
perhaps,  because  the  precipitate  is  less  continuous  and  more  loose  and 
flaky,  partly  because  it  is  soluble  in  excess  of  proteid,  and  therefore 
allows  the  unattached  molecules  to  penetrate  deeply,  while  the  lead 
albuminate  remains  on  the  surface  of  the  membrane.  The  metals  also 
differ  in  their  toxicity,  and  a  trace  of  mercury  is  sufficient  to  kill  a 
cell,  whereas  a  larger  amount  of  lead  may  be  absorbed  by  it  without 
injury. 

In  addition  salts  which  have  a  very  strong  affinity  for  water  with- 
draw fluid  from  the  cells  and  thus  act  more  strongly  on  them  than 
others  which  have  not  this  character ;  for  example  dried  alum  is  much 
more  destructive  to  the  tissues  with  which  it  comes  in  contact  than 
alum  containing  its  ordinary  water  of  crystallization. 

The  different  metallic  salts  therefore  vary  in  their  local  action 
within  wide  limits  —  from  the  formation  of  mildly  astringent  mem- 
branes to  the  production  of  widespread  necrosis  and  destruction  of  tissue. 

The  insoluble  salts  come  into  less  intimate  contact  with  the  tissues, 
and  have  much  less  effect ;  but  many  of  them  are  slowly  formed  into 
albuminates  and  may  then  act  as  irritants  or  astringents. 

The  most  powerful  corrosive  salts  of  any  metal  are  those  which  are 
most  rapidly  dissociated  into  ions,  that  is,  the  chlorides  and  nitrates, 
provided  they  are  soluble.  The  sulphates  are  much  less  irritant,  be- 
cause they  are  less  readily  dissociated,  and  perhaps  because  the  sul- 
phuric acid  may  fail  to  penetrate  the  cells  owing  to  its  being  less 
volatile  and  its  anion  having  less  permeating  power  than  that  of  hy- 
drochloric or  nitric  acid.  (See  page  535.)  The  iodides  and  bromides 
are  generally  regarded  as  less  irritant  than  the  chlorides,  but  are  less 
frequently  used  and  less  well  known. 

The  least  corrosive  of  the  salts  of  the  metals  are  those  formed  with 
the  slowly  dissociated  organic  acids,  such  as  the  acetates,  tartrates  or 
citrates.  When  these  are  united  with  a  metal  which  in  itself  is  not  a 
very  active  poison,  such  as  lead,  they  are  almost  purely  astringent. 
On  the  other  hand,  the  acetate  of  silver  or  of  mercury  tends  to  be 
irritant  and  corrosive,  from  the  poisonous  action  of  these  metals  on  the 


624  THE  HEAVY  METALS. 

tissues.  In  any  case,  the  acetates  are  less  irritant  than  the  correspond- 
ing chlorides  and  nitrates,  provided  these  are  equally  soluble. 

The  local  action  also  varies  in  the  same  salt  of  different  metals. 
Lead  is  the  most  astringent  of  the  metals  ordinarily  used  in  solution, 
while  mercury  salts  have  little  or  no  astringent  action,  owing  to  their 
specific  poisonous  action  on  the  cells.  Iron  and  alum  approach  most 
nearly  to  lead,  then  copper,  zinc  and  silver,  and  at  a  longer  interval 
mercury. 

It  is  impossible  to  arrange  the  metallic  salts  as  either  astringents  or 
irritants,  because  in  every  instance  the  effect  varies  with  the  concen- 
tration, and  with  many  other  features,  such  as  the  condition  of  the 
surface  to  which  they  are  applied,  and  the  quantity  of  proteid  with 
which  they  come  in  contact  before  they  actually  reach  the  living  mem- 
brane. 

Of  the  salts  in  common  use  the  most  astringent  are  lead  acetate  and 
alum  ;  the  most  irritant  are  the  perchloride  and  the  nitrate  of  mercury, 
the  chlorides  of  zinc,  copper,  tin  and  antimony,  while  the  chlorides 
of  iron,  sulphates  of  copper,  zinc,  iron  and  manganese,  the  acetates 
of  copper  and  zinc  and  the  nitrates  of  silver  and  lead  are  astringents 
when  applied  in  very  dilute  solution,  but  tend  to  irritate  and  corrode 
in  larger  quantities.  In  most  cases  the  effects  of  the  last  group  are 
made  up  of  a  mixture  of  astringent  and  irritant  action. 

The  insoluble  preparations  of  mercury  tend  to  irritate  and  corrode 
the  surfaces  to  which  they  are  applied,  but  the  insoluble  salts  of  the  other 
metals  are  generally  astringent.  It  is  difficult  to  determine  how  far  the 
so-called  astringent  and  protective  action  of  these  insoluble  substances 
is  due  to  the  formation  of  albuminates,  and  how  far  to  their  acting 
mechanically  as  protective  coverings  over  irritated  surfaces,  but  the 
latter  factor  is  undoubtedly  the  more  important  in  many  instances. 

The  precipitation  induced  by  the  astringents  involves  only  the  surface 
layer  of  cells,  but  the  membrane  formed  protects  the  part  from  me- 
chanical and  chemical  irritation,  and  thus  lessens  congestion  and  inflam- 
mation. In  addition  several  authors l  have  found  that  the  astringent 
salts  contract  the  vessels  of  the  frog's  mesentery  by  direct  action  on 
their  coats,  and  have  inferred  that  the  same  constriction  is  induced  in 
the  mucous  membranes,  when  they  are  applied  to  them.  Schiitz2 
found  that  the  secretion  of  the  frog's  skin  and  tongue  is  lessened 
when  these  parts  are  washed  with  astringent  metallic  salts,  and  it  is 
quite  possible  that  when  these  are  applied  to  inflamed  membranes,  they 
may  constrict  the  vessels  and  lessen  the  secretions,  as  well  as  form  a 
protective  membrane.  When  irritation  is  induced,  the  vessels  of  course 
dilate,  and  congestion  and  exudation  follow. 

The  local  action  is  due  to  the  formation  of  albuminate  compounds 
and  the  liberation  of  acid.  If  the  metal  be  applied  in  the  form  of  an 
albuminate,  this  irritation  is  almost  entirely  absent  except  in  so  far  as 

lEosenstirn,  Eossbach's  Pharmakologische  Untersuchungen,  ii.,  p.  84.  Hei-nz,  Vir- 
chow's  Arch.,  cxvi.,  p.  220. 

2  Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii.,  p.  202, 


THE  HEAVY  METALS.  625 

the  poisonous  action  of  the  metal  may  cause  necrosis  and  consequent 
irritation  and  inflammation.  The  double  salts  of  the  metals  are  also 
less  liable  to  irritate,  because  they  do  not  precipitate  albumin,  and 
their  dissociation  only  occurs  slowly  and  is  not  confined  to  the  point 
of  application.  Of  course  if  these  double  salts  are  decomposed  by 
acids,  as  in  the  stomach,  they  may  act  as  irritants. 

The  salts  of  the  heavy  metals  are  often  only  slowly  Absorbed. 
Mercury  is  again  an  exception,  but  even  mercury  does  not  induce  gen- 
eral symptoms  until  many  hours  after  its  administration.  The  other 
metals  given  by  the  mouth  pass  through  the  alimentary  canal  for  the 
most  part  unabsorbed.  In  recent  years  it  has  been  disputed  whether 
iron,  manganese,  copper  and  other  metals  are  absorbed  at  all,  but 
investigation  with  more  accurate  methods  has  shown  that  iron  and 
manganese  pass  into  the  tissues  from  the  alimentary  tract,  and  it  seems 
probable  that  a  small  proportion  of  most  of  the  metals  finds  its  way  into 
the  blood.  At  the  same  time  there  is  no  question  that  the  great  pro- 
portion of  most  of  the  metals  passes  through  unabsorbed,  and  is  devoid 
of  any  effect  except  from  its  local  action.  It  is  probable  that  the 
small  quantity  taken  up  by  the  stomach  and  intestine  is  first  formed 
into  proteid  compounds  in  every  instance,  but  there  is  very  little 
known  as  to  the  process.  When  there  is  any  lesion  of  the  stomach  and 
intestine,  and  particularly  when  the  salt  induces  irritation  and  con- 
gestion itself,  much  more  of  the  metal  is  taken  up  than  by  the  normal 
epithelium.  But  even  in  the  most  favorable  circumstances  little  of 
the  metal  is  absorbed,  and  in  acute  poisoning  the  symptoms  arise  from 
the  local  irritation  and  corrosion,  and  only  to  a  smaller  extent  from 
the  general  action  of  the  metal. 

If  the  absorption  of  the  metals  is  slow,  their  Excretion  progresses 
even  more  gradually,  and  repeated  administration  leads  to  their  accum- 
ulation in  the  tissues  and  thus  to  intoxication.  The  metal  seems  to 
leave  the  blood  very  rapidly,  and  to  become  stored  up  in  various 
organs,  chiefly  the  liver,  to  a  less  extent  the  spleen,  kidney,  and  bone 
marrow.  While  some  of  the  metal  is  deposited  in  the  liver  and  other 
organs,  another  part  is  excreted,  for  the  most  part  along  the  alimentary 
tract.  Thus  it  is  found  in  the  saliva  and  gastric  secretion,  to  a  much 
larger  amount  generally  in  that  of  the  lower  parts  of  the  small  intes- 
tine, in  the  ca3cuni  and  in  the  large  bowel.  A  comparatively  small 
amount  escapes  with  the  urine.  Some  metals  have  been  detected  in 
very  small  quantity  in  the  milk,  and  there  is  reason  to  suppose  that 
traces  are  eliminated  by  the  other  cutaneous  secretions. 

The  General  Action  of  the  heavy  metals  in  man  is  often  elicited 
only  by  their  prolonged  ingestion,  but  it  has  been  studied  in  animals 
by  the  intravenous  or  subcutaneous  injection  of  the  albuminates  or  of 
the  double  salts,  which  do  not  precipitate  the  proteids.  The  ordinary 
salts  cannot  be  used,  because  the  precipitated  albumin  of  the  blood 
causes  embolism,  and  this  obscures  the  symptoms.  The  symptoms  of 
acute  metallic  poisoning  elicited  thus  in  animals  generally  resemble 
fairly  closely  those  of  chronic  poisoning  in  man.  Of  course  the  ana- 
40 


626  THE  HEA  VY  METALS. 

tomical  lesions  induced  in  the  latter  by  the  constant  presence  of  small 
quantities  of  metals  in  the  nutritive  fluids,  can  only  be  induced  to  a 
limited  extent  in  such  experiments. 

Even  when  the  heavy  metals  are  injected  into  the  blood  in  consid- 
erable quantity,  the  symptoms  are  often  late  in  appearing,  in  the  case 
of  aluminium  only  after  several  days,  so  that  the  slowness  of  the  ab- 
sorption from  the  intestine  is  not  the  only  explanation  of  the  delay  in 
the  onset  of  the  intoxication. 

The  general  symptoms  of  metallic  poisoning,  as  distinguished  from 
those  due  to  the  local  action  at  the  point  of  application,  arise  chiefly 
from  the  central  nervous  system,  and  from  the  excretory  passages  — 
the  alimentary  canal  and  the  kidney.  Metallic  poisoning  always  in- 
duces disturbance  of  the  Stomach  and  Intestine,  manifested  by  loss  of 
appetite,  pain  and  discomfort  in  the  abdomen,  nausea,  vomiting  and 
purging.  In  some  cases  no  lesion  of  the  canal  is  observed  post  mortem, 
but  in  the  great  majority  congestion  and  swelling  of  the  mucous  mem- 
branes of  the  stomach  and  intestine  is  seen,  or  the  whole  surface  may 
be  covered  by  a  diphtheritic  membrane  composed  of  necrosed  cells 
and  inflammatory  exudate.  Beneath  this  haemorrhages  occur,  and  if 
the  animal  live  long  enough,  ulcers  are  formed,  so  that  the  whole  con- 
dition can  scarcely  be  distinguished  from  that  of  dysentery.  Some 
metals  act  strongly  on  the  mouth  and  salivary  glands,  salivation  being 
one  of  the  earliest  features  of  mercury  poisoning.  The  lining  mem- 
brane of  the  mouth  becomes  congested  and  inflamed,  and  numerous 
shallow  ulcers  are  formed  in  it. 

The  heavy  metals  thus  seem  to  have  a  specific  action  along  the 
alimentary  tract  quite  independent  of  the  local  action  induced  when 
they  are  swallowed.  This  is  connected  with  their  excretions  along  it, 
although  it  seems  inadvisable  in  the  present  state  of  knowledge  to  say 
that  they  irritate  the  digestive  tract  because  they  are  excreted  in  it. 
One  or  two  metals,  notably  lead,  cause  constipation  and  colic  when 
they  are  absorbed  into  the  blood,  but  under  certain  circumstances  they 
too  induce  purgation. 

Another  organ  which  suffers  from  the  circulation  of  metals  in  the 
blood  is  the  Kidney.  Comparatively  little  of  the  metal  is  excreted  in 
the  urine,  but  it  is  found  that  most  of  this  class  act  as  diuretics  in  small 
quantities.  Somewhat  larger  doses  irritate  the  renal  epithelium,  and 
albumin  appears  in  the  urine,  along  with  casts  and  in  severe  cases 
blood  cells  and  haemoglobin.  If  this  irritation  of  the  secretory  cells 
be  long  continued,  it  sets  up  a  secondary  inflammation  of  the  intersti- 
tial tissue,  and  cirrhosis  of  the  kidney  results. 

The  Circulation  is  differently  affected  by  different  metals,  or  at  any 
rate,  the  effects  on  the  heart  and  vessels  are  described  differently  by 
the  writers  on  the  subject.  Very  often  the  heart  is  affected  only  in 
the  last  stages  of  poisoning,  and  it  is  impossible  to  determine  how  far 
its  failure  is  due  to  direct  action,  and  how  far  to  the  general  disorder 
of  the  nutrition.  The  blood-pressure  invariably  falls  towards  the 
fatal  issue  of  the  intoxication,  and  as  a  general  rule,  a  slow  fell  is 


THE  HEAVY  METALS.  627 

observed  from  the  beginning.  This  fall  in  blood-pressure  has  been 
ascribed  to  the  heart  action,  to  depression  of  the  vaso-motor  centre, 
and  to  paralysis  of  the  splanchnic  terminations  in  the  mesenteric  ves- 
sels. It  may  doubtless  be  induced  by  different  factors  in  the  different 
forms  of  intoxication,  but  there  is  no  question  that  it  is  partly  due  to 
the  dilatation  of  the  vessels  of  the  intestines  and  stomach  from  the 
inflammation  of  these  organs. 

Several  metals  have  been  found  to  lessen  the  alkalinity  of  the  Blood 
by  increasing  the  amount  of  lactic  acid  in  it,  but  this  does  not  seem 
a  common  feature  in  metallic  poisoning.  The  general  malnutrition 
from  the  gastro-intestinal  action  renders  it  impossible  to  determine 
whether  the  metals  alter  the  metabolism  of  the  body  through  directly 
affecting  the  cells,  but  it  is  not  improbable  that  this  is  the  case,  for 
the  loss  of  weight  is  often  too  rapid  to  be  explained  by  the  starvation 
alone. 

The  Central  Nervous  System  is  always  affected  more  or  less  by  the 
presence  of  the  metals  in  the  blood.  As  a  general  rule,  the  symptoms 
are  a  mixture  of  those  of  stimulation  of  certain  divisions  with  those  of 
paralysis  of  others.  Several  metals  induce  disturbance  of  the  psychical 
centres,  manifested  in  delirium,  hallucinations  and  mania,  or  in  stupor 
and  coma.  Convulsions  of  all  forms  indicate  that  the  motor  areas  of 
the  brain,  the  basal  ganglia  and  the  spinal  cord  are  affected;  thus 
epileptiform  convulsions,  chorea,  clonic  and  tonic  spasms  occur  from 
metallic  poisoning.  In  several  instances  actual  lesions  of  the  brain 
cells  have  been  shown  to  be  caused  by  the  ingestion  of  the  metals. 
They  often  cause  general  weakness,  or  paresis  of  certain  groups  of 
muscles,  and  in  addition  to  their  specific  action  on  the  nervous  centres, 
they  may  induce  a  peripheral  neuritis  (lead).  The  muscles  do  not 
seem  to  be  so  readily  affected  in  general  poisoning,  although  a  solution 
of  a  non-irritating  metallic  salt  generally  paralyzes  muscles  suspended 
in  it. 

Therapeutic  Uses. — In  therapeutics  only  mercury  and  iron  are  largely 
employed  for  their  effects  after  absorption,  while  the  others  have  a 
more  or  less  extensive  use  for  their  local  effects  as  astringents,  irritants, 
caustics  or  styptics.  Iron  is  not  prescribed  for  its  general  action  on  the 
organs,  but  to  supply  the  place  of  food-irons  in  the  formation  of  hae- 
moglobin. Mercury  is  used  for  its  specific  effect  in  syphilis,  and  some 
of  its  preparations  have  been  advised  as  diuretics.  Not  infrequently 
the  local  action  of  the  heavy  metals  is  supposed  to  be  induced  after  ab- 
sorption, and  prescriptions  are  met  with  containing  lead  or  iron  which 
are  intended  to  stay  haemorrhage  from  the  lungs  or  from  the  kidneys. 
It  ought  to  be  recognized,  however,  that  lead  or  iron  is  absorbed  only 
in  minute  quantities,  and  that  they  have  no  predilection  for  the  bleed- 
ing points.  If  they  were  capable  of  coagulating  the  blood  after  ab- 
sorption, and  thus  stopping  haemorrhage,  they  would  certainly  do  so  in 
the  portal  circulation  and  would  not  be  carried  to  the  lungs  or  kidney 
before  they  acted.  As  a  matter  of  fact,  however,  they  never  reach  the 
blood  except  in  forms  in  which  they  have  no  astringent  or  styptic  action. 


628  THE  HE  A  VY  METALS. 

Many  of  the  metallic  salts  are  powerful  antiseptics,  partly  no  doubt 
from  their  coagulating  the  proteids  of  the  microbes,  but  also  from  a 
specific  poisonous  action  on  them,  which  is  quite  distinct  from  their 
precipitating  action.  As  a  general  rule  the  antiseptic  power  varies 
with  the  amount  of  dissociation  of  the  salt,  that  is,  with  the  number  of 
metallic  ions  present  in  the  solutions,  although  the  undissociated  mole- 
cule also  seems  to  have  some  influence,  and  a  salt  which  is  dissociated 
with  difficulty  may  in  some  instances  make  up  for  this  drawback  by 
the  more  intense  toxicity  of  the  metal.1  The  most  widely  used  metallic 
antiseptics  are  the  mercurial  salts,  in  particular  the  perchloride,  but 
other  metals  have  recently  begun  to  play  a  more  important  role  in  sur- 
gery than  heretofore.  Almost  incredibly  small  quantities  of  some  of 
the  metals  have  been  found  to  be  rapidly  fatal  to  some  of  the  algae,  the 
bacteria,  and  the  infusoria.  Thus  one  part  of  the  perchloride  of  mer- 
cury in  one  million  parts  of  water  kills  spirogyra,  one  of  the  simpler 
algfe,  and  water  distilled  from  copper  vessels  is  rapidly  destructive  to 
it.  Israel  and  Klingmann  2  hung  small  pieces  of  copper  foil  in  water 
for  a  few  hours,  and  then  diluted  this  water  a  hundred  times  and  found 
it  still  poisonous  to  many  lower  organisms.  Silver  was  less  active  and 
lead  still  less  so.  The  amount  of  copper  in  the  original  solution  was 
too  small  to  be  recognized  by  any  chemical  test,  much  more  so  then  in 
the  further  diluted  portion.  These  results,  which  were  first  obtained 
by  Naegeli,  and  which  have  been  confirmed  by  other  observers  besides 
Israel  and  Klingmann,  indicate  that  certain  lower  organisms  are  much 
more  sensitive  to  the  action  of  copper,  and  probably  of  other  metals, 
than  the  more  highly  organized  plants  and  animals.  Further  exami- 
nation of  their  effects  as  antiseptics  in  medicine  and  surgery  is  certainly 
desirable.  Other  curious  effects  on  the  growth  of  bacteria  have  been  ob- 
served by  Bolton  and  Brown,3  who  found  that  a  piece  of  metal  placed 
on  a  culture  of  microbes  in  gelatin  causes  curious  alternating  zones 
of  intense  growth  and  of  sterility.  These  observations  have  recently 
been  extended  by  Thiele  and  Wolff,4  who  state  that  silver,  mercury  and 
copper  plates  prevent  the  growth  of  microbes  owing  to  minute  traces 
of  these  metals  being  dissolved  in  the  medium.  Several  other  heavy 
metals  —  iron,  lead,  zinc,  tin,  gold,  platinum  and  aluminum  —  proved 
devoid  of  action.  A  practical  application  of  this  bactericidal  action  of 
the  metals  has  been  made  by  the  introduction  of  solutions  of  colloid 
forms  of  silver  and  mercury  as  antiseptics.  Some  of  these  colloid 
metals  have  proved  destructive  to  simple  organisms  in  extremely  dilute 
solution,  while  in  more  concentrated  forms  they  are  inferior  to  the 
ordinary  salts  of  the  metals. 

1  Kronlg  u.  Paul.     Ztschr.  f.  Hygiene,  xxv.,  p.  1. 
2Virchow's  Arch.,  cxlvii.,  p.  293. 

3 Transactions  of  the  Assoc.  of  Araer.  Physicians,  xii.,  p.  488. 
4  Arch.  f.  Hygiene,  xxxiv.,  p.  43. 


ANTIMONY.  629 

I.     ANTIMONY. 

The  preparations  of  antimony  played  a  much  more  important  role  in 
therapeutics  in  the  earlier  part  of  last  century  than  at  the  present  time, 
and  promise  to  be  used  to  a  still  more  limited  extent  in  the  future. 
In  many  respects  they  resemble  arsenic  in  their  effects,  and  may  be 
looked  upon  as  forming  a  link  between  it  and  the  salts  of  the  other 
heavy  metals.  The  salt  most  commonly  used  is  tartar  emetic,  or  the 
double  tartrate  of  antimony  and  potassium  [K(SbO)C4H4O6] .  The 
effects  of  this  salt  were  at  one  time  believed  to  be  due  in  part  to  the 
potassium,  but  have  been  shown  to  be  those  of  the  antimony  alone. 
Many  other  compounds  of  antimony  have  been  used  in  therapeutics, 
and  several  others  are  still  found  in  the  pharmacopoeias,  but  they  differ 
for  most  part  from  tartar  emetic  only  in  the  rapidity  of  their  action. 

Tartar  emetic,  like  other  double  salts,  is  not  corrosive,  because  it 
does  not  precipitate  proteids  except  in  acid  solutions,  in  which  it  is 
decomposed  into  simpler  forms.  The  chloride  of  antimony,  on  the 
other  hand,  readily  dissociates  the  antimony  ion  and  is  a  powerful 
caustic  when  applied  to  the  skin  or  the  mucous  membranes. 

When  rubbed  on  the  Skin,  however,  tartar  emetic  causes  redness, 
and  a  papular  eruption,  which  later  passes  into  vesicles  and  pustules. 
If  the  application  be  further  persisted  in,  these  pustules  may  become 
confluent  and  form  small  abscesses,  and  later  cause  extensive  necrosis 
and  ulceration  of  the  skin.  The  points  of  origin  of  the  papules  are  the 
openings  of  the  cutaneous  glands  and  the  hair  follicles. 

Symptoms.  —  Tartar  emetic  has  a  slight,  acrid  taste,  and  in  very 
small  quantities  causes  no  symptoms,  except  some  perspiration.  In 
somewhat  larger  doses  its  ingestion  is  followed  by  nausea  and  vomiting, 
with  very  marked  depression  and  the  usual  accompaniments  of  emesis, 
such  as  salivation,  profuse  perspiration  and  acceleration  of  the  pulse 
(see  Apomorphine,  page  235).  In  antimonial  poisoning  the  vomiting 
is  violent  and  continuous,  the  ordinary  contents  of  the  stomach  being 
first  evacuated,  and  then  a  slimy  mucous  fluid,  which  may  later  con- 
tain blood.  In  some  cases  it  is  said  that  no  gastric  symptoms  are 
observed,  but  these  must  be  exceedingly  rare.  The  vomiting  is  ac- 
companied by  profuse  watery  diarrhoea,  resembling  that  of  arsenical 
poisoning,  and  by  great  muscular  weakness  and  collapse.  The  pulse 
may  be  somewhat  accelerated  at  first,  but  is  weak,  and  later  becomes 
slow  and  irregular.  The  skin  is  cold  and  covered  with  a  clammy  per- 
spiration, and  cyanosis  of  the  face  and  extremities  is  generally  marked. 
The  respiration  is  slow  and  may  be  irregular,  the  voice  weak  and 
husky,  the  temperature  is  depressed,  and  the  patient  falls  into  a  coma- 
tose condition,  which  deepens,  until  after  a  few  weak  convulsive  move- 
ments the  respiration  ceases.  The  urine  is  sometimes  increased  in  the 
beginning  of  the  poisoning,  but  later  may  become  scanty  or  entirely 
suppressed.  It  often  contains  albumin. 

The  minimum  fatal  dose  of  tartar  emetic  is  doubtful,  as  the  greater 
part  of  the  poison  is  generally  removed  by  vomiting.  Recovery  has 


630  THE  HEA  VY  METALS. 

been  observed  after  very  large  quantities,  while  in  other  cases  0.1  G. 
(2  grs.)  has  proved  fatal. 

Chronic  antimonial  poisoning  is  very  rare  and  difficult  to  diagnose.  The 
symptoms  are  depression,  headache,  giddiness  and  confusion,  drowsiness  and 
indistinct  sight.  The  appetite  is  bad,  and  the  patient  complains  of  heavi- 
ness, discomfort,  or  pain  in  the  region  of  the  stomach,  general  weakness  and 
exhaustion.  Profuse  diarrhoea  may  be  present,  rapid  loss  of  flesh,  albumi- 
nuria  and  finally  collapse.  Pustular  eruptions  have  been  observed  from  the 
prolonged  internal  use  of  tartar  emetic. 

Action,  —  Many  of  the  symptoms  of  antimonial  poisoning,  the  pro- 
fuse perspiration,  salivation  and,  to  some  extent  at  least,  the  collapse, 
are  manifestly  secondary  to  the  Emetic  Action,  and  the  cause  of  the 
vomiting  has,  accordingly,  been  repeatedly  investigated.  It  may  be 
stated  at  once  that  some  authors  attribute  the  vomiting  to  a  central 
action,  but  that  the  majority  are  inclined  to  regard  it  as  mainly  due  to 
irritation  of  the  stomach.  Large  doses  of  antimony  affect  the  stomach 
and  bowel  in  the  same  way  as  arsenic,  inducing  hypersemia  and  swell- 
ing and  loosening  of  the  epithelium,  but  smaller  quantities  such  as  are 
used  in  therapeutics  do  not  seem  to  cause  any  obvious  lesion-  It  is 
found  that  tartar  emetic  injected  hypodermically  or  intravenously 
causes  nausea  and  vomiting,  but  much  larger  quantities  are  required 
than  are  requisite  when  the  drug  is  given  by  the  mouth.  This  indi- 
cates a  direct  action  on  the  stomach,  rather  than  on  the  centre  for 
vomiting,  and  this  view  is  supported  by  the  fact  that  antimony  is 
found  in  the  stomach  and  intestine  when  it  is  injected  intravenously. 
The  obvious  explanation  would  therefore  seem  to  be  that  antimony 
given  by  the  mouth  acts  as  a  gastric  irritant,  and  causes  vomiting, 
while  when  it  is  injected  intravenously  it  is  carried  to  the  stomach, 
and  again  causes  irritation  with  the  same  result.  The  whole  of  the 
antimony  swallowed  acts  at  once  on  the  stomach,  while  only  a  part 
of  that  injected  exerts  its  action  on  it,  and  larger  doses  are  therefore 
necessary  when  the  poison  is  administered  in  the  latter  way. 

This  explanation  is  opposed,  however,  to  an  observation  made  by  Orfila, 
who  found  that  when  the  stomach  was  excised  and  replaced  by  a  dead  blad- 
der, tartar  emetic  still  caused  the  movements  of  vomiting,  which  even 
expressed  the  fluid  in  the  bladder.  Of  course  no  antimony  could  be  excreted 
into  the  bladder,  and  no  irritation  or  reflexes  could  arise  from  it.  Again 
Mosso  states  that  when  the  vagus  nerves  are  cut  below  the  diaphragm,  tar- 
tar emetic  fails  to  cause  vomiting  when  it  is  swallowed,  but  large  doses  have 
their  usual  effect  when  injected  into  a  vein.  These  observations  appear  at 
first  sight  to  indicate  that  tartar  emetic  acts  centrally,  but  it  has  been  sug- 
gested that  although  the  poison  could  not  act  on  the  stomach  in  Orfila' s 
experiment  it  might  cause  vomiting  by  causing  irritation  of  some  other  part 
of  the  alimentary  tract.  As  regards  Mosso' s  results,  the  relation  of  the 
vagus  nerve  to  vomiting  is  still  so  obscure  that  it  is  dangerous  to  draw  any 
inference  from  such  experiments.  On  the  whole  the  evidence  goes  to  show 
that  the  emesis  is  due  to  irritation  of  the  gastric  mucous  membrane  by  the 
antimony. 

The  action  of  tartar  emetic  on  the  Stomach  has  been  explained  by 
supposing  that  the  acid  gastric  juice  decomposes  the  double  salt  and 


ANTIMONY.  631 

that  the  chloride  thus  formed  acts  as  a  corrosive  in  the  same  way  as 
the  chlorides  of  the  other  heavy  metals.  This,  however,  fails  to  ex- 
plain the  fact  that  the  same  effects  are  met  with  in  the  intestine,  in 
which  no  such  acid  fluid  exists,  and  that  vomiting  is  induced  readily 
when  the  gastric  juice  is  neutral  in  reaction  (Mosso).  A  more  prob- 
able explanation  is  that  antimony  has  a  specific  irritant  effect  on  the 
mucous  membranes  of  the  stomach  and  bowel,  similar  to  that  of  ar- 
senic. The  irritation  is  greater,  however,  and  is  induced  more  rapidly, 
so  that  vomiting  is  caused  much  more  easily.  At  the  same  time,  an- 
timony is  more  slowly  absorbed  than  arsenic,  so  that  its  action  re- 
mains confined  to  the  stomach,  and  as  the  vomiting  removes  much  the 
greater  part  of  the  poison,  the  intestine  remains  unharmed  except 
when  large  quantities  have  been  swallowed  and  the  emesis  is  from  any 
cause  insufficient.  In  chronic  poisoning  ulceration  of  the  small  intes- 
tine is  said  to  occur,  especially  around  the  solitary  follicles  and  Pey- 
er*s  patches. 

The  acceleration  of  the  Pulse  seen  after  tartar  emetic  is  due  for  the  most 
part  to  the  emetic  action  and  not  to  the  absorption  of  the  drug.  When  in- 
jected into  a  vein  in  animals,  antimony  causes  a  slow  and  weak  pulse, 
although  this  is  preceded  in  some  cases  by  slight  acceleration.  The  action 
is  a  direct  one  on  the  cardiac  muscle,  as  maybe  seen  by  perfusing  an  excised 
frog's  heart  with  blood  containing  some  tartar  emetic.  The  cardiac  nerves 
do  not  seem  to  be  affected. 

The  Blood-pressure  falls  throughout  the  experiment,  partly  owing  to  the 
weakness  of  the  heart  but  chiefly  owing  to  an  action  on  the  vascular  mecha- 
nism similar  to  that  described  under  arsenic.  Here  again  it  is  doubtful 
whether  the  effect  is  due  to  the  vaso-motor  centre  or  to  the  peripheral  nerves 
and  muscle  of  the  vessels,  but  the  latter  are  certainly  involved,  for  stimula- 
tion of  the  spinal  cord  fails  to  contract  the  mesenteric  vessels. 

The  Respiration  is  often  slightly  accelerated  at  first,  and  may  be  shallow 
and  irregular  from  the  nausea  ;  but  in  cases  of  poisoning  it  becomes  slow  and 
labored,  and  eventually  ceases  along  with  the  heart.  The  respiratory  centre 
is  perhaps  affected  directly  to  some  extent,  but  the  changes  in  the  breathing 
are  probably  due  for  the  most  part  to  the  disturbance  of  the  circulation,  and 
to  the  action  on  the  alimentary  canal.  The  statement  made  by  some  of  the 
older  writers  that  antimony  caused  hepatization  of  the  lungs,  has  been  shown 
to  be  incorrect. 

The  Central  Nervous  System  is  depressed  by  antimony  in  the  frog, 
spontaneous  movements  persisting  after  the  reflexes  have  disappeared, 
according  to  some  authors.  This  has  been  interpreted  to  mean  that  antimony 
paralyzes  the  sensory  part  of  the  cord  or  its  connection  with  the  motor  cell, 
while  leaving  the  connections  between  the  latter  and  the  brain  intact ;  but 
the  statement  itself  requires  further  confirmation.  The  paralysis  is  due  to 
the  direct  action  of  antimony  on  the  nerve  cells  and  not  to  the  disordered 
circulation,  for  frogs  poisoned  with  antimony  are  paralyzed  sooner  than 
others  in  which  the  circulation  is  entirely  destroyed  by  the  excision  of  the 
heart.  The  effect  of  antimony  on  the  central  nervous  system  of  the  mammals 
is  more  obscure,  for  it  is  impossible  to  ascertain  how  far  the  changes  are  due 
to  direct  action  and  how  far  they  are  attributable  to  the  disturbance  of  the 
circulation  and  the  alimentary  canal.  There  is  reason  to  believe,  however, 
that  the  poison  depresses  to  some  extent  the  nerve  cells  here  also.  Accord- 
ing to  Schaffer,  the  cells  of  the  spinal  cord  undergo  a  degeneration  marked 
by  the  disappearance  of  the  chromatin  in  chronic  antimonial  poisoning. 


632  THE  HEA  VY  METALS. 

The  Depression  and  Collapse  of  antimony  poisoning  are  caused  by  the 
gastric  effects  and  the  slowed  circulation  acting  on  the  central  nervous  sys- 
tem, and  not,  as  is  sometimes  stated,  to  the  peripheral  nerves  and  muscles 
being  affected.  The  voluntary  muscular  tissue  is  undoubtedly  weakened  to 
some  extent  in  the  frog,  but  only  after  large  doses  and  at  a  late  stage.  The 
muscles  then  contract  somewhat  more  weakly  than  normally,  and  are  more 
readily  fatigued. 

Many  of  the  Secretions  are  increased  by  tartar  emetic,  such  as  the  per- 
spiration, the  saliva  and  the  mucous  secretion  of  the  respiratory  tract.  This 
is  not  due  to  any  direct  action  on  the  glands,  for  the  same  effect  is  induced 
by  anything  which  causes  vomiting.  (See  Apomorphine,  page  235.)  The 
urine  is  sometimes  increased  by  antimony,  at  other  times  it  is  diminished  or 
suppressed.  This  is  perhaps  due  to  a  preliminary  stimulation  of  the  renal 
epithelium,  which  passes  into  acute  irritation  when  much  of  the  drug  is  ab- 
sorbed. The  action  on  the  urinary  secretion  is  not  very  marked,  however. 

The  irritant  action  of  tartar  emetic  on  the  Skin  when  it  is  applied 
to  it  in  ointment,  has  been  explained  by  the  double  salt  being  broken 
up  by  the  acid  formed  in  the  decomposing  secretions,  and  an  analogy 
has  been  drawn  between  it  and  the  irritant  effects  in  the  stomach.  In 
support  of  this  it  is  said  that  the  addition  of  alkalies  to  the  tartar 
emetic  ointment  prevents  the  formation  of  pustules.  This  does  not 
seem  a  very  happy  explanation,  although  it  accounts  for  the  formation 
of  pustules  at  the  openings  of  the  skin  glands.  The  double  salts  of 
other  metals,  however,  which  would  form  irritants  in  the  same  way  as 
tartar  emetic  have  no  special  effect  on  the  mouths  of  the  gland  ducts. 
Nunn  finds  a  specific  effect  on  the  skin  of  the  frog  when  tartar  emetic 
is  injected,  similar  to  that  induced  by  arsenic,  but  more  rapid  in  its 
onset,  and  this  may  explain  the  pustulant  action.  A  pustular  erup- 
tion is  said  to  be  induced  in  some  cases  when  antimony  is  taken 
internally.  Pustules  also  occur  in  the  oesophagus  when  tartar  emetic 
is  swallowed,  and  irritation  of  the  mouth  and  swelling  of  the  lips 
have  been  observed. 

The  effects  of  antimony  on  the  Nutrition  have  not  been  so  carefully 
examined  as  those  of  arsenic,  but,  as  far  as  is  known,  present  a  strong  re- 
semblance to  them.  Thus  fatty  degeneration  of  many  organs  is  induced  by 
its  prolonged  use,  the  nitrogen  of  the  urine  is  found  to  be  increased,  and  the 
glycogen  disappears  from  the  liver.  Very  small  quantities  of  antimony 
given  repeatedly  are  said  to  increase  the  glycogen  and  fat  of  the  liver,  with- 
out apparently  altering  the  nitrogen  of  the  urine. 

The  fall  in  Temperature  after  antimony  is  often  very  considerable,  amount- 
ing in  animals  to  6°  C.  in  the  course  of  a  few  hours.  It  is  explained  by  the 
slowness  of  the  circulation  and  by  the  general  depression  and  collapse  and 
profuse  perspiration. 

Antimony  is  Absorbed  from  the  skin  very  slowly,  and  from  the  stomach 
and  intestine.  It  passes  into  the  tissues  much  more  gradually  than  arsenic, 
however,  and  its  action  on  the  stomach,  can,  therefore,  be  elicited  without 
danger  of  its  causing  general  symptoms.  After  absorption  antimony  is 
found  in  considerable  quantity  in  the  liver,  which  stores  it  up  for  some 
time.  It  is  excreted  into  the  stomach  and  intestine,  in  the  urine,  and,  it  is 
said,  in  the  bile  and  milk. 

The  Chloride  of  Antimony  (SbCl,)  differs  from  tartar  emetic  chiefly  in  being 
a  violent  corrosive,  which  combines  to  form  albuminates  and  thus  acts  like 


ANTIMONY.  633 

the  other  salts  of  the  heavy  metals,  and  also  tends  to  withdraw  fluid  from 
the  superficial  tissues,  when  it  is  applied  in  a  concentrated  solution.  The 
other  compounds  of  antimony  act  like  the  double  tartrate,  except  that  most  of 
them  are  much  slower  in  their  effects.  Stibine  or  antinioniuretted  hydrogen 
(SbH3)  differs  entirely  from  arsine  (AsH3)  in  its  action,  which  is,  however, 
equally  poisonous.  It  has  very  rarely  been  examined,  except  in  an  impure  form, 
and  the  symptoms  are  imperfectly  known. 

PREPARATIONS. 

ANTIMONII  ET  POTASSII  TARTRAS  (U.  S.  P.),  ANTTMONIUM  TARTARATUM 
(B.  P.),  tartar  emetic,  tartarated  antimony  ((KSbOC4H4O6)2  -f  H2O)  forms 
colorless,  transparent  crystals,  or  a  white  granulated  powder,  without  odor, 
and  having  a  sweet,  afterwards  disagreeable,  metallic  taste,  soluble  in  17 
parts  of  cold  water,  insoluble  in  alcohol.  Dose  as  a  diaphoretic  0.002-0.008 
G.  (jV-i-  gr.),  as  an  emetic  0.03-0.1  G.  Q-2  gr.). 

VINTJM  ANTIMONII  (U.  S.  P.),  VINUM  ANTIMONIALE  (B.  P.),  4  parts  of 
tartar  emetic  in  one  thousand  (U.  S.  P.),  in  875  parts  (B.  P.).  0.6-2  c.c. 
(10-30  mins.),  diaphoretic  ;  4-15  c.c.  (1-4  drs.),  emetic. 

Tartar  emetic  is  also  contained  in  the  compound  syrup  of  squills  U.  S.  P. 

Antimonii  Oxidum  (B.  P.),  (Sb2O3),  a  heavy,  gray,  insoluble  and  tasteless 
powder.  0.05-0.1  G.  (1-2  grs.). 

Pulvis  Antimonialis  (B.  P.),  James'  powder,  consists  of  antimony  oxide  1  part 
to  2  parts  of  phosphate  of  calcium.  0.15-0.3  G.  (3-6  grs.). 

Antimoniwm  Nig  rum  Piirificatum  (B.  P.)  (Sb2S3),  a  heavy  grayish-black  powder, 
odorless,  tasteless,  and  insoluble  in  water.  0.015-0.06  G.  Q-l  gr.). 

Antimonium  Sulphuratum  (B.  P.),  Kermes  mineral,  consists  of  antimony  sul- 
phide (Sb2S3)  with  a  small  amount  of  oxide  (Sb203) — an  amorphous,  reddish-brown 
powder,  odorless,  tasteless,  and  insoluble  in  water.  0.06-0.3  G.  (1-5  grs.). 

Pilula  Hydrargyri  Subchloridi  Composita  (B.  P.),  Plummer's  Pills,  compound 
calomel  pill,  8  grains  contain  nearly  2  grains  each  of  calomel  and  of  sul- 
phurated antimony.  4-8  grs. 

Therapeutic  Uses.  —  Antimony  is  used  to  a  much  less  extent  in  med- 
icine than  was  formerly  the  case.  In  the  seventeenth  century  it  was 
prescribed  so  widely  and  was  believed  to  do  so  much  harm,  that  the 
graduates  in  medicine  of  Heidelberg  were  required  to  take  an  oath 
never  to  use  it.  At  present  it  is  used  to  a  limited  extent  as  an  emetic, 
but  is  slow  in  action  and  induces  greater  depression  and  more  pro- 
longed nausea  than  the  other  drugs  which  are  prescribed  for  this  pur- 
pose, such  as  apomorphine,  ipecacuanha,  or  sulphate  of  copper.  It  is 
therefore  seldom  used  to  evacuate  the  stomach  in  cases  of  poisoning  or 
of  foreign  bodies  in  the  stomach  or  oesophagus.  Its  expectorant  action 
is  taken  advantage  of  in  acute  bronchitis  in  which  the  secretion  of  the 
bronchial  mucous  membrane  is  insufficient,  but  it  is  of  less  value  when 
the  secretion  is  abundant.  In  commencing  bronchitis  tartar  emetic  is 
sometimes  given  until  vomiting  occurs,  and  then  continued  in  smaller 
doses  and  at  longer  intervals. 

It  is  also  used  as  a  diaphoretic  to  some  extent,  in  the  same  doses  as  are 
prescribed  as  expectorants,  but  it  has  been  almost  entirely  supplanted  by 
pilocarpine  for  this  purpose.  James'  powder  was  especially  popular  as  a 
diaphoretic,  but  is  now  seldom  employed. 

In  acute  fever  antimony  was  formerly  largely  used  as  a  depressant,  more 
especially  when  delirium  was  a  marked  feature.  The  object  was  to  produce 


634  THE  HEAVY  METALS. 

a  mild  collapse,  but  the  treatment  has  been  entirely  abandoned  by  most 
authorities,  and  probably  did  more  harm  than  good.  Acute  lobar  pneu- 
monia was  almost  universally  treated  by  tartar  emetic  at  one  time,  and  an 
attempt  has  recently  been  made  to  revive  this  treatment,  but  without  suc- 
cess. 

Antimony  has  been  advised  instead  of  arsenic  in  the  internal  treatment  of 
skin  disease,  but  it  is  impossible  to  state  at  present  how  far  it  is  capable  of 
replacing  the  more  widely  used  drug. 

In  all  cases  in  which  there  is  marked  depression  or  weakness,  in  which 
the  stomach  or  bowel  is  disordered,  or  in  which  the  circulation  is  feeble,  the 
preparations  of  antimony  are  contraindicated. 

Tartar  emetic  was  formerly  used  in  ointment  (one  part  to  four)  as  a  skin 
irritant,  but  its  continued  application  has  led  in  several  cases  to  diffuse  sub- 
cutaneous abscess,  and  sometimes  to  necrosis  of  bone,  so  that  the  tartar 
emetic  ointment  has  passed  into  desuetude. 

In  cases  of  Antimonial  Poisoning,  emetics  are  seldom  required,  but 
the  stomach  may  be  washed  out  by  means  of  the  stomach  tube,  if 
vomiting  is  not  present,  and  a  purge  may  be  given  to  remove  the  poison 
in  the  bowel.  Tannic  acid  is  used  to  precipitate  the  antimony  in  the 
stomach,  and  the  tannate  formed  must  be  washed  out.  A  form  of  tan- 
nic  acid  which  is  usually  available  in  emergencies  is  strong  tea,  which 
is  also  useful  as  a  stimulant  for  the  collapse.  Lime  or  magnesia  may 
be  used  to  precipitate  the  antimony  instead  of  tannic  acid. 

BIBLIOGRAPHY. 

Ackermann.     Virchow's  Arch.,  xxv.,  p.  531. 
Radziejewski.     Arch.  f.  Anat.  u.  Phys.,  1871,  p.  472. 
Saikowski.     Virchow's  Arch.,  xxxiv.,  p.  73. 
Soloweitschyk.     Arch.  f.  exp.  Path.  u.  Pharm.,  xii.,  p.  438. 
Kobert.     Ibid.,  xv.,  p.  36. 
Grimm.     Pfliiger's  Arch.,  iv.,  p.  205. 
Harnack.     Munch,  med.  Woch.,  1892,  p.  179. 
Ringer  and  Murrell.     Journ.  of  Physiol.,  i.  p.  241. 
Stock  and  Guttmann.     Ber.  d.  deutsch.  chem.  Gesell.,  xxxvii.,  p.  884. 
Thumas.     Virchow's  Arch.,  cxxiii.,  p.  66. 
Mosso.     Schmidt's  Jahrbuch,  clxix.,  p.  236. 

Chittenden  and  Blake.  Studies  from  the  Lab.  of  Physiolog.  Chem.  Sheffield  Scientific 
School,  ii.,  p.  87;  iii.,  p.  106. 

Kubeler.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxvii.,  p.  451. 


II.    MERCURY. 

Mercury,  one  of  the  most  powerful  inorganic  poisons,  has  been  used 
in  medicine  for  a  long  time  and  in  a  large  variety  of  forms.  Some 
differences  are  observed  in  the  action  of  these,  but  all  of  them  induce 
the  same  general  results,  the  differences  existing  only  in  their  local 
effects,  and  being  due  to  the  salts  differing  in  solubility  and  dissocia- 
bility.  A  soluble  salt,  such  as  the  perchloride,  comes  into  more  inti- 
mate contact  with  the  tissues,  and  therefore  acts  more  powerfully 
locally,  and  is  also  absorbed  more  rapidly  and  in  larger  amount  than 
calomel,  which  is  entirely  insoluble  in  water.  Both  the  local  and  the 
general  effects  of  the  perchloride  are  more  marked  than  those  of  calo- 


MERCURY.  635 

mel,  therefore,  but  when  sufficient  mercury  in  the  form  of  calomel  is 
absorbed  into  the  tissues,  the  general  effects  are  the  same  as  if  an  equal 
quantity  had  been  taken  up  as  perchloride. 

Mercury  is  absorbed  and  circulates  in  the  blood  in  the  form  of  the 
albuminate,  which  is  insoluble  in  water,  but  is  rendered  soluble  by  ex- 
cess of  proteid,  and  also  by  chloride  of  sodium  in  such  quantities  as 
are  met  with  in  the  tissues.  The  solubility  of  the  albuminate  ex- 
plains how  mercury  is  absorbed  so  much  more  quickly  than  any  of  the 
other  heavy  metals,  and  at  the  same  time  it  may  account  .in  part  for  its 
greater  corrosive  action.  The  corrosion  is  due  to  some  extent  to  the 
acid  constituent  of  the  preparation,  but  this  is  not  greater  than  that  of 
an  equally  soluble  and  equally  dissociable  combination  of  the  acid  with 
another  metal.  The  mercurial  ion  itself  is  also  corrosive,  and  its  de- 
structive action  is  the  more  powerful  because  the  precipitate  formed  with 
proteids  is  less  insoluble  in  the  surrounding  fluids  of  the  body  and  is 
therefore  more  flocculent  and  affords  less  protection  to  the  surface, 
than  those  formed  by  the  other  heavy  metals.  The  mercurial  action  is 
consequently  not  limited  to  the  surface  of  a  tissue  but  extends  into  the 
deeper  cells.  The  highly  corrosive  action  of  the  mercury  ion  has  been 
ascribed  to  its  great  affinity  for  the  amido-cornpounds  which  are  con- 
tained in  the  albumin  molecule.  Liebermann  has  also  shown  that  it 
has  a  special  affinity  for  lecithalbumin,  and  it  is  possible  that  this  may 
play  an  important  role  both  in  the  absorption  and  in  the  slow  excretion 
of  the  metal. 

The  albuminate  is  formed  rapidly  when  such  soluble  salts  as  the 
perchloride  come  in  contact  with  the  tissues,  and  the  local  corrosion  is 
greater  and  the  absorption  more  rapid  than  when  an  insoluble  salt  is 
ingested.  A  good  deal  of  dispute  has  arisen  as  to  the  absorption  of  the 
insoluble  salts  of  mercury,  and  it  is  frequently  stated  that  calomel  is 
first  changed  to  the  perchloride  by  the  action  of  the  hydrochloric  acid 
of  the  stomach  and  by  the  chlorides  of  the  tissues,  and  that  only  then 
is  the  albuminate  formed.  There  is,  however,  no  sufficient  evidence 
that  the  perchloride  is  formed  from  the  chloride,  and  such  a  change  is 
not  necessary  to  explain  its  absorption,  for  the  proteids  of  the  tissues 
can  act  on  calomel  as  such,  and,  forming  the  soluble  albuminate,  allow 
it  to  be  absorbed.  It  has  been  asserted  of  late  that  when  calomel  is 
injected  hypodermically,  the  leucocytes  take  it  up  and  carry  it  off  as 
they  do  any  other  foreign  insoluble  body,  and  it  is  quite  possible  that 
they  may  take  it  up  in  the  same  way  from  the  alimentary  canal.  At 
the  same  time  the  quantity  of  calomel  which  comes  into  intimate  con- 
tact with  the  tissues  is  much  smaller  than  in  the  case  of  the  soluble 
perchloride,  and  a  smaller  proportion  of  calomel  is  absorbed  therefore. 
In  the  same  way  other  insoluble  preparations  of  mercury  are  absorbed 
in  the  form  of  aibuminates,  and  even  the  metal  may  be  oxidized  and 
absorbed  when  it  is  applied  to  the  living  surfaces  or  injected  into  the 
blood  in  a  state  of  fine  division.  Thus  the  inhalation  of  mercury  vapor 
by  the  lungs  leads  to  general  poisoning,  often  of  a  very  malignant  type, 
and  mercury  rubbed  into  very  fine  globules,  and  applied  in  ointment 


636  THE  HEAVY  METALS. 

to  the  skin,  passes  into  the  gland  ducts  and  along  the  roots  of  the  hairs, 
and,  after  being  oxidized,  is  dissolved  and  absorbed  into  the  tissues,  in 
which  it  causes  the  typical  mercurial  effects. 

Symptoms.  —  Acute  Mercurial  Poisoning  occurs  only  from  the  use  of 
soluble  preparations,  and  in  particular  from  the  perchloride  of  mercury 
or  corrosive  sublimate.  Many  cases  have  arisen  from  this  poison  being 
swallowed  accidentally  or  with  suicidal  intent,  but  of  late  years  an 
almost  equal  number  has  arisen  from  the  perchloride  being  used  as  an 
antiseptic  wash  for  large  cavities.  When  corrosive  sublimate  is  swal- 
lowed in  poisonous  quantity,  the  patient  complains  at  once  of  the  harsh, 
metallic  taste,  which  is  followed  by  burning  pain  in  the  mouth,  throat 
and  stomach.  Nausea  and  vomiting  set  in  very  soon,  and  the  vomited 
matter  may  contain  shreds  of  mucous  membrane  and  blood.  Diar- 
rhoea and  violent  tenesmus,  with  watery  or  bloody  stools,  often  con- 
taining shreds  of  membrane,  may  be  among  the  early  symptoms,  or 
may  only  occur  after  twenty-four  hours.  These  symptoms  from  the 
alimentary  canal  are  accompanied  by  collapse,  with  a  small,  thready, 
sometimes  irregular  pulse,  shallow,  irregular,  rapid  respiration,  cold, 
clammy  skin,  pinched  features,  and  sunken  eyes.  The  temperature  is 
often  subnormal,  but  sometimes  fever  is  observed,  although  this  is 
attributed  by  many  to  concurrent  disease.  The  consciousness  is  usually 
unaffected,  but  in  some  cases  somnolence,  giddiness,  or  more  rarely 
anxiety  and  restlessness  have  been  observed.  The  urine  is  much 
diminished  and  complete  anuria  often  occurs  in  a  few  hours.  If  the 
urine  is  not  completely  suppressed,  it  generally  contains  albumin,  renal 
epithelium,  casts,  and  more  rarely  sugar.  Death  may  occur  within  an 
hour  from  shock,  but  more  frequently  the  patient  survives  several  days 
or  even  one  or  two  weeks,  the  symptoms  of  intestinal  corrosion  and  of 
renal  irritation  continuing,  until  he  finally  sinks  from  exhaustion. 

When  acute  poisoning  occurs  from  the  absorption  of  corrosive  subli- 
mate from  wounds,  the  symptoms  of  corrosion  of  the  mouth  and  stomach 
are  absent  at  first,  but  the  dysenteric  symptoms  and  the  renal  inflam- 
mation are  produced  in  the  same  way  as  when  the  poison  is  swallowed. 
Here  again  the  patient  may  die  within  a  few  hours,  but  more  fre- 
quently survives  for  several  days,  and  in  the  latter  case  the  symptoms 
towards  the  end  partake  of  the  character  of  chronic  poisoning.  In 
particular,  salivation  and  stomatitis  set  in  in  the  course  of  a  few  days. 
These  also  occur  when  the  poison  is  swallowed,  although  they  are  more 
liable  to  be  overlooked,  from  the  cauterization  produced  in  the  mouth 
by  the  local  action. 

Chronic  Poisoning.  —  A  much  more  frequently  observed  form  of 
poisoning  is  that  induced  by  the  prolonged  medicinal  use  of  mercury. 
It  may  arise  from  any  of  the  preparations,  and  from  any  form  of  ap- 
plication, although  some  methods  of  administration  are  credited  with 
being  less  liable  to  induce  it  than  others.  Thus  inunction  with  mer- 
curial ointment  and  the  use  of  calomel  internally  are  both  more  liable 
to  cause  the  severer  forms  of  stomatitis  than  is  corrosive  sublimate. 
A  single  hypodermic  injection  of  an  insoluble  preparation  may  induce 


MERCURY.  637 

it  in  susceptible  persons,  because  the  mercury  is  only  slowly  absorbed, 
and  passes  into  the  tissues  as  gradually  as  if  it  were  given  by  the  mouth 
regularly  for  several  days.  This  chronic  poisoning  or  Mercurialism  is 
due,  not  to  the  local  action,  but  to  the  effects  of  the  drug  after  absorp- 
tion. It  is  much  more  liable  to  occur  in  certain  people  than  in  others, 
but  may  follow  the  abuse  of  mercury  in  any  case,  and  the  cause  of  the 
abnormal  susceptibility  to  mercury  is  unknown.  When  mercurialism 
begins  to  be  manifested,  the  drug  ought  to  be  stopped,  or  the  dose 
much  reduced,  until  the  symptoms  disappear.  Formerly  it  was  be- 
lieved that  the  earlier  symptoms  of  mercurial  poisoning  had  to  be  in- 
duced in  the  cure  of  syphilis,  but  in  modern  therapeutics  every  effort 
is  made  to  avoid  them.  The  first  symptoms  generally  arise  from  the 
mouth  and  throat,  the  patient  complaining  of  a  metallic  taste,  and  of  a 
feeling  of  numbness  or  soreness  of  the  tongue  and  gums.  The  breath 
has  an  unpleasant  fetid  odor,  the  tongue  is  swollen  and  thickly  coated, 
the  gums  are  soft,  swollen  and  often  of  a  dark  bluish-red  or  gray 
color  and  the  flow  of  saliva  is  augmented.  If  the  medication  be 
continued  as  was  often  done  formerly,  ulcers  appear  on  the  gums 
and  on  the  sides  of  the  tongue  where  it  comes  in  contact  with  the 
teeth,  especially  if  these  are  carious,  and  on  the  mucous  membrane  of 
the  cheeks  ;  the  salivation  increases  and  irritates  the  lips  and  the  skin 
where  it  is  exposed  to  the  secretion.  If  the  administration  of  mercury 
be  still  persisted  in,  the  teeth  become  loose  and  fall  out,  gangrene  of  the 
gums,  lips  and  throat,  and  necrosis  of  part  or  even  of  the  whole  jaw 
may  follow,  and  may  prove  fatal  by  exhaustion  and  inanition  due  to 
the  difficulty  in  swallowing  and  to  the  complete  absence  of  desire  for 
food.  The  milder  forms  of  stomatitis  and  salivation  are  observed  in  a 
large  proportion  of  cases  of  syphilis  treated  with  mercury,  according 
to  some  authors  in  30  per  cent,  or  more.  It  may  be  avoided,  to  some 
extent,  at  least,  by  scrupulous  cleanliness  of  the  mouth  and  teeth,  by 
the  filling  of  carious  teeth,  and  by  using  a  2-4  per  cent,  solution  of 
chlorate  of  potash  as  a  mouth  wash. 

The  stomach  and  intestine  also  suffer  in  chronic  mercury  poisoning. 
The  patient  often  complains  of  loss  of  appetite,  and  occasionally  of  a 
feeling  of  weight  and  discomfort  in  the  stomach,  nausea  and  vomiting, 
general  weakness  and  loss  of  flesh.  Colic  and  diarrhoea  are  frequently 
observed,  or  diarrhoea  and  constipation  may  alternate.  These  symp- 
toms are  naturally  more  liable  to  occur  from  the  administration  of 
mercury  by  the  mouth  than  by  other  channels,  as  here  the  action  after 
absorption  is  reinforced  by  the  direct  local  effects.  Some  fever  is 
sometimes  noted,  but  this  is  secondary  to  the  affection  of  the  mouth, 
bowel  or  skin,  and  is  not  directly  attributable  to  the  mercury. 

Occasionally  skin  eruptions  are  seen  when  mercury  is  given  by  the 
mouth,  but  much  more  frequently  when  it  is  applied  to  the  skin.  In 
the  latter  case  they  are  not  limited  to  the  point  of  application,  although 
they  often  begin  from  it  and  spread  over  a  large  surface  of  the  body. 
They  are  said  to  occur  often  without  any  other  symptom  of  poisoning, 
except  the  fever  and  discomfort  which  they  induce  themselves.  They 


638  THE  HEAVY  METALS. 

vary  greatly  in  form,  consisting  of  small  reddish  spots,  large  red  ery- 
thematous  surfaces,  urticaria,  or  eczema,  each  of  these  occurring  alone 
or  in  succession,  and  being  usually  followed  by  desquamation.  The 
eruption  generally  lasts  only  1-3  weeks,  but  in  some  cases  has  not  en- 
tirely disappeared  until  three  months  after  its  first  appearance,  and  in 
others  has  returned  repeatedly  afterwards.  It  is  said  to  have  been 
induced  occasionally  by  a  single  dose  of  calomel. 

The  urine  is  often  somewhat  increased,  but  may  be  decreased  after- 
wards, and  it  not  infrequently  contains  albumin,  although  the  proportion 
of  cases  in  which  this  occurs  is  much  disputed,  and  the  amount  in  the  urine 
is  generally  very  small.  Glycosuria  is  much  rarer  in  man,  but  has  been 
frequently  observed  in  rabbits  after  prolonged  treatment  with  mercury. 

It  is  still  a  matter  of  doubt  how  far  the  sexual  organs  are  involved 
in  mercury  poisoning.  According  to  some  authorities  disturbances  of 
the  menstruation  and  even  complete  amenorrhoea  have  been  observed, 
and  abortion  is  also  stated  to  have  been  caused  by  it. 

A  general  condition  of  cachexia  may  be  induced  by  the  presence  of 
these  disorders,  and  is  marked  by  pallor,  anaemia,  emaciation,  weak- 
ness and  restlessness,  with  a  tendency  to  fainting  and  disturbed  sleep. 
The  pulse  is  small,  weak  and  quick,  sometimes  irregular,  and  the  pa- 
tient often  complains  of  breathlessness. 

Affections  of  the  central  nervous  system  are  rarely  induced  now  by 
the  abuse  of  mercury  in  therapeutics,  but  are  mentioned  by  some  of 
the  earlier  writers,  and  still  occur  in  the  case  of  workers  in  mercury 
mines,  in  mirror,  barometer  and  thermometer  factories,  and  in  other 
manufactories  in  which  mercury  is  used  and  its  fumes  are  inhaled  by 
the  workmen  for  prolonged  periods.  One  of  these  affections  is  the 
mercurial  erethism,  a  condition  of  abnormal  irritability,  timidity  or 
shyness,  accompanied  by  great  muscular  weakness,  and  sometimes 
developing  into  sleeplessness,  delirium  and  transitory  hallucinations. 
Another  well-known  form  is  the  mercurial  tremor>  which  affects  the 
hands  and  arms  first,  later  the  legs,  and  sometimes  extends  over  all  the 
muscles  of  the  body.  Shooting  pains  along  the  nerves  or  in  the  joints 
are  sometimes  complained  of,  circumscribed  areas  of  partial  anaesthe- 
sia, amblyopia,  anosmia  or  deafness  have  been  described,  and  in  some 
cases  localized  paralysis  of  the  muscles  of  the  arm  or  leg  has  been 
induced.  These  last  differ  from  the  paralysis  of  lead  or  arsenic  poi- 
soning in  the  fact  that  no  wasting  of  the  muscles  is  observed,  and  the 
electrical  reaction  remains  normal.  According  to  Letulle  they  are  due 
to  the  destruction  of  the  myeline  sheath  of  the  peripheral  nerves,  the 
axis  cylinder  remaining  intact. 

The  symptoms  of  mercurial  poisoning,  both  acute  and  chronic,  in 
animals,  resemble  those  in  man  so  closely  that  it  is  unnecessary  to  de- 
scribe them  further. 

Action  —  Lower  Forms  of  Life.  —  The  action  of  mercury  on  proteids 
extends  to  all  forms  of  living  matter.  Whenever  the  metal  comes  into 
intimate  contact  with  albumins,  it  forms  the  albuminate  and  destroys 
life.  This  poisonous  action  is  naturally  much  more  evident  when  solu- 


MERCURY.  639 

ble  preparations  are  used  than  when  the  oxides  or  calomel  are  in  ques- 
tion. Thus  corrosive  sublimate  in  a  solution  of  one  part  in  50,000 
destroys  infusoria  in  some  20  minutes,  and  even  one  part  in  one  mil- 
lion kills  algse  in  the  course  of  a  few  days.  The  bacteria  are  some- 
what more  resistant  than  these  forms,  but  corrosive  sublimate  is  said 
to  delay  the  development  of  some  of  these  in  a  solution  of  one  part  in 
one  million,  and  the  anthrax  bacillus  fails  to  grow  in  blood  which  con- 
tains one  part  in  8,000.  A  solution  of  one  part  in  one  thousand  is 
generally  regarded  as  capable  of  disinfecting  fluids  completely  in  the 
course  of  a  few  hours,  but  there  is  no  question  that  the  germicidal 
power  of  corrosive  sublimate  has  been  much  overestimated.  Thus 
Geppert  found  that  the  spores  of  anthrax  could  be  exposed  to  the  ac- 
tion of  a  one  per  cent,  solution  for  many  hours  and  still  develop  as 
soon  as  the  mercury  was  entirely  removed.  There  is  no  doubt,  how- 
ever, that  corrosive  sublimate  and  the  other  soluble  salts  of  mercury 
are  among  the  most  powerful  antiseptics  at  present  available.  The 
insoluble  preparations  are  less  poisonous,  ovying  to  the  difficulty  in 
bringing  them  into  intimate  contact  with  the  microbes,  but  calomel 
has  been  shown  to  have  some  effect  as  an  intestinal  antiseptic. 

In  the  Higher  Animals  and  in  Man  the  same  destructive  effects  are 
induced  by  the  mercury  preparations.  The  corrosion  of  the  mouth, 
throat  and  stomach  when  the  perchloride  is  swallowed,  has  already 
been  mentioned.  When  it  is  applied  to  the  other  mucous  membranes, 
Bimilar  effects  are  obtained,  and  when  it  is  injected  hypodermically, 
even  in  dilute  solution,  it  induces  intense  pain,  swelling  and  inflam- 
mation, which  is  rarely  followed  by  suppuration,  but  which  may 
result  in  the  formation  of  cicatrices.  Stronger  solutions  injected  into 
animals  often  cause  the '  formation  of  cheesy  abscesses,  and  even  dry 
necrosis  of  the  skin  and  underlying  tissue.  The  hypodermic  or  in- 
tramuscular injection  of  insoluble  preparations  is  more  liable  to  cause 
abscess  formation,  because  the  mercury  is  slowly  absorbed  and  has 
therefore  more  time  to  induce  its  irritant  effects. 

When  solutions  of  corrosive  sublimate  are  applied  to  the  skin,  they 
cause  a  feeling  of  numbness  very  often ;  but  when  very  strong  solu- 
tions come  in  contact  with  tender  parts  of  the  skin,  and  in  particular, 
when  the  salt  itself  is  allowed  to  lie  in  contact  with  it  for  any  length 
of  time,  deep  corrosion,  necrosis  and  sloughing  may  follow.  Even  the 
insoluble  preparations  are  liable  to  set  up  irritation  when  they  are 
rubbed  into  the  skin,  especially  if  there  is  any  pre-existing  tendency 
to  cutaneous  eruption. 

After  absorption,  mercury  acts  more  especially  on  the  alimentary 
tract  and  on  the  kidneys,  although  other  organs  are  not  exempt  from 
its  effects. 

The  Salivation  and  Stomatitis,  which  are  so  frequently  seen  under 
mercurial  medication,  are  obviously  not  due  to  the  local  action  of  the 
drug  on  its  way  to  the  stomach,  for  they  occur  equally  readily  when  it 
is  applied  by  hypodermic  injection  or  by  inunction.  The  salivation  is 
apparently  due  to  the  direct  action  of  the  mercury  on  the  secretory 


640  THE  HEAVY  METALS. 

apparatus,  for  it  often  appears  before  any  other  symptom  and  is  cer- 
tainly not  the  reflex  effect  of  the  irritation  of  the  mouth.  The  saliva 
is  sometimes  excreted  in  enormous  amounts,  many  litres  of  it  being 
poured  out  in  the  course  of  twenty-four  hours.  It  contains  mercury, 
and  has  therefore  a  metallic  taste,  and  tends  to  irritate  the  lips  and 
skin  where  it  comes  in  contact  with  them.  In  extreme  cases  it  leads 
to  sleeplessness  from  its  accumulating  in  the  back  of  the  throat  and 
awakening  the  patient  with  a  feeling  of  suffocation.  The  stomati- 
tis is  likewise  due  to  the  excretion  of  mercury  by  the  saliva  and  by 
the  other  mucous  secretions  of  the  mouth  and  throat.  The  irritation 
caused  by  the  metal  leads  to  excoriations,  and  these  to  the  formation 
of  ulcers,  particularly  where  microbes  are  present  in  large  numbers,  as 
around  carious  teeth.  The  necrosis  of  the  jaws  arises  from  these  ulcers, 
penetrating  to  the  bone  and  setting  up  periostitis,  for  mercury  in  itself 
has  no  specific  action  on  the  bone  such  as  has  been  mentioned  under 
phosphorus. 

Mercury  has  less  direct  effect  on  the  Stomach,  though  congestion  and 
even  small  haemorrhages  in  cases  of  poisoning  indicate  that  it  is  not 
entirely  immune ;  the  loss  of  appetite  and  malnutrition  in  chronic 
poisoning  are  ascribed  to  the  presence  of  mercury  in  the  saliva  rather 
than  to  its  affecting  the  gastric  functions  directly.  In  the  Intestine,  on 
the  other  hand,  mercury  is  apparently  excreted  in  large  amount,  and 
induces  very  distinct  lesions.  The  parts  affected  are  the  caecum  and 
colon,  while  the  small  intestine  very  often  escapes  almost  entirely. 
The  action  of  mercury  is  evidenced  by  hypenemia,  redness  and  swell- 
ing of  the  mucous  membrane,  which  later  develop  into  necrotic  sur- 
faces and  ulcers  along  the  folds ;  these  lend  it  an  appearance  almost 
indistinguishable  from  that  of  chronic  dysentery  and  may  eventually 
end  in  perforation.  The  symptoms  from  the  intestine  are  in  accord- 
ance with  the  lesions,  consisting  in  constant  purging  with  very  fluid, 
sometimes  rice-water  stools,  intense  pain  and  tenesmus,  blood  and  frag- 
ments of  mucous  membrane  in  the  faeces. 

Small  doses  of  mercurials  given  by  the  mouth  act  as  Purges,  causing 
soft  stools  generally  without  pain  or  straining.  The  insoluble  prepa- 
rations are  used  for  this  purpose,  as  they  act  least  on  the  stomach,  and 
the  mercurial  purges  par  excellence  are  calomel  and  the  metallic  prep- 
arations —  blue  pill  and  gray  powder.  This  effect  is  apparently  due  to 
their  acting  as  intestinal  irritants  from  their  specific  action  on  the  in- 
testine. They  apparently  do  not  remain  long  enough  in  the  stomach 
to  be  dissolved,  and  besides  seem  to  have  less  tendency  to  induce  irri- 
tation here.  In  the  intestine,  on  the  other  hand,  their  longer  sojourn 
and  special  affinity  for  the  epithelium,  leads  to  their  partial  solution 
and  to  their  irritant  action  being  developed.  A  small  proportion  of 
these  insoluble  preparations  is  absorbed  from  the  intestine,  but  the 
great  mass  is  thrown  out  unchanged  in  the  stools,  and  thus  very  large 
doses  of  calomel  sometimes  induce  no  serious  symptoms.  Mercury  acts 
in  the  intestine  even  when  the  bile  is  suppressed,  and  the  stools  are 
often  of  a  greenish  color,  which  has  been  ascribed  to  a  metallic  com- 


MERCURY.  641 

pound  formed  in  the  bowel,  but  which  is  really  due  to  bile  pigment. 
This  is  ordinarily  decomposed  by  the  microbes  in  the  intestine  with 
the  formation  of  the  fsecal  pigment,  but  mercury  from  its  antiseptic 
properties  prevents  the  growth  of  the  microbes,  and  the  bile  therefore 
appears  in  the  stools  undecomposed  and  possessed  of  its  ordinary 
color. 

The  mercurial  purges,  and  in  particular  calomel,  have  often  been 
credited  with  increasing  the  secretion  of  the  Bile,  but  this  has  been 
shown  to  be  incorrect,  for  Stadelmann  (in  animals)  and  Pfaff  (in  man) 
found  that  the  mercurial  preparations  had  no  effect  on  the  secretion 
escaping  from  a  biliary  fistula.  The  belief  probably  arose  from  the 
green  color  of  the  stools,  but  this,  as  already  mentioned,  is  due,  not  to 
the  increase  of  the  bile,  but  to  its  being  preserved  from  putrefaction 
in  the  intestine.  There  is,  in  fact,  no  sufficient  experimental  or  clini- 
cal evidence  that  the  liver  is  in  any  way  affected  directly  by  mercury. 
The  "  biliousness  "  which  is  so  often  relieved  by  calomel  or  blue  pill, 
is  due,  not  to  the  liver,  but  to  disorder  of  the  alimentary  tract. 

Mercury  has  no  such  powerful  effect  on  the  Unorganized  ferments  of 
digestion  as  it  has  upon  the  microbes,  for  though  large  amounts  of  the 
soluble  preparations  precipitate  the  pepsin  in  artificial  digestion  experi- 
ments, smaller  quantities  have  little  such  effect.  Calomel  has  no  action 
on  the  digestive  ferments,  but  retards  the  putrefaction  in  the  intestine, 
and  thus  limits  the  decomposition  of  the  food.  Its  antiseptic  action 
is  aided  by  the  increased  peristalsis  which  follows  its  use,  and  which 
removes  the  decomposing  mass  from  the  canal.  In  fact,  the  lessened 
amount  of  double  sulphates  in  the  urine  which  follows  the  use  of 
calomel,  may  be  ascribed  as  much  to  its  purgative,  as  to  its  antiseptic 
power. 

Another  organ  which  is  powerfully  affected  by  mercury  is  the  Kid- 
ney. A  moderate  dose  of  calomel  induces  marked  diuresis,  particu- 
larly in  cases  in  which  there  is  a  large  accumulation  of  fluid  in  the 
body,  as  in  dropsy  from  heart  disease.  In  other  forms  of  dropsy, 
such  as  that  arising  from  hepatic  cirrhosis,  or  from  renal  disease,  it  is 
less  reliable,  although  it  not  infrequently  increases  the  flow  of  urine  in 
these  cases  also.  AYhen  purging  follows  the  administration  of  the 
mercurial,  less  diuretic  effect  is  observed. 

In  normal  individuals  and  in  animals  the  diuretic  action  is  gener- 
ally much  weaker,  although  some  recent  work  has  shown  that  it  can 
be  elicited  easily  in  rabbits  (Cohnstein).  In  view  of  the  fact  that 
mercurial  preparations  have  an  irritant  action  on  the  kidney,  it  would 
seem  that  the  increased  secretion  of  urine  induced  by  calomel  and  by 
other  mercurials  is  most  probably  to  be  ascribed  to  a  direct  action  on 
the  epithelium. 

In  acute   mercurial   poisoning,  when   death  does   not   follow  in  the 

course  of  a  few  hours,  anuria  is  often  observed  both  in  man  and  animals. 

This  anuria  is  due  to  the  renal  changes,  which  are  found  to  consist  in 

necrosis  of  the  epithelium  of  the  tubules  in  some  parts  of  the  cortex. 

41 


642  THE  HEAVY  METALS. 

The  whole  organ  is  congested  and  the  glomeruli  are  in  a  state  of  acute 
inflammation,  but  the  necrosed  tubules  are  the  most  prominent  feature. 
Very  generally  in  the  rabbit,  less  often  in  the  dog  and  in  man,  these 
are  filled  with  a  deposit  of  phosphate  of  calcium,  occasionally  in- 
termixed with  some  chalk.  According  to  some  pathologists,  it  is 
deposited  first  in  the  tubules  and  only  when  these  are  filled  does  it 
force  its  way  into  the  cells,  but  a  more  probable  view  is  that  it  is  thrown 
out  in  the  necrosed  cells,  and  as  these  break  up,  passes  into  the  tubules. 
It  may  be  remarked  in  passing  that  several  other  poisons,  such  as  bis- 
muth and  aloin,  occasionally  induce  this  deposit  of  lime  in  the 
kidneys. 

These  renal  symptoms  have  been  observed  most  frequently  in  cor- 
rosive sublimate  poisoning,  either  by  the  mouth,  or  from  absorption 
from  a  wound.  The  more  slowly  absorbed,  insoluble  preparations  ap- 
parently do  not  often  accumulate  in  sufficient  quantity  in  the  blood  to 
induce  such  severe  effects.  At  the  same  time,  albumin  or  casts  are 
very  often  observed  in  the  urine  from  the  treatment  of  syphilitic  pa- 
tients with  mercury  in  any  form,  although  it  is  stated  that  this  is  less 
liable  to  occur  when  soluble  preparations  are  injected  hypodermically 
than  after  inunction  or  the  use  of  insoluble  salts  subcutaneously.  The 
more  marked  the  action  on  the  intestine,  the  less  destruction  of  the 
kidney  is  observed  in  cases  of  severe  poisoning. 

The  lime  deposited  in  the  kidney  has  suggested  the  idea  that  mercury  has 
a  specific  action  on  Bone,  consisting  in  the  absorption  of  the  calcium,  and  an 
attempt  has  been  made  to  demonstrate  this  action  by  estimating  the  lime 
salts  in  bone  after  mercury,  and  comparing  the  amount  with  that  of  normal 
animals  of  the  same  size.  No  action  on  bone  has  been  established,  however,  and 
the  explanation  of  the  renal  deposit  as  due  to  decalcification  of  the  bones  has 
been  shown  to  be  incorrect  by  Klemperer,  who  found  that,  instead  of  being 
oversaturated  with  lime  which  it  deposits  in  the  kidney,  the  blood  actually  con- 
tains a  somewhat  smaller  amount  of  lime  than  normally.  The  lime  deposited  in 
the  kidney  is  evidentally  drawn  from  that  normally  circulating  in  the  blood  ;  in 
necrosed  tissue  from  other  causes  lime  is  very  often  deposited,  although  not  so 
rapidly  as  in  mercury  poisoning.  Large  doses  given  repeatedly  lead  to  an 
increase  in  the  size  and  number  of  the  vessels  of  the  bone-marrow  and  the  fat 
cells  atrophy  rapidly  ;  later,  gelatinous  degeneration  follows  and  the  cellular  ele- 
ments of  the  marrow  disappear. 

Mercury  seems  to  have  comparatively  little  direct  action  on  the  Circulation 
in  cases  of  poisoning,  and  most  of  the  changes  in  the  pulse  are  to  be  ascribed 
rather  to  the  shock  and  collapse,  or  in  chronic  poisoning  to  the  cachexia  and 
malnutrition,  than  to  any  direct  effects  on  the  heart  and  vessels  ;  in  some  cases 
of  acute  poisoning,  however,  patches  of  fatty  degeneration  have  been  found  in 
the  heart.  In  the  frog  large  doses  of  soluble  salts  slow  and  weaken  the  heart, 
and  mercury  salts  injected  into  the  blood  vessels  of  mammals  have  been  found  to 
cause  a  sudden  descent  of  the  blood-pressure  and  paralysis  of  the  heart.  Sub- 
cutaneously injected  into  animals,  the  soluble  salts  reduce  the  blood-pressure 
more  gradually,  but  at  the  end  a  very  sudden  descent  to  zero  occurs.  The  action 
is  in  part  on  the  heart  muscle,  in  part  on  the  peripheral  vessels. 

The  Respiration  is  also  only  affected  indirectly.  In  chronic  mercury  poi- 
soning, marked  breathlessness  is  sometimes  observed  and  has  been  ascribed  by 
Kussmaul  to  the  general  muscular  weakness. 


MERCURY.  643 

The  action  of  mercury  on  the  Nervous  System  is  very  obscure.  In 
acute  poisoning  the  intellect  often  remains  clear  to  the  end,  and  no 
symptoms  pointing  to  any  direct  affection  of  the  central  nervous 
system  are  observed.  In  chronic  poisoning,  however,  the  higher  cen- 
tres are  undoubtedly  involved  in  the  effects,  as  is  shown  by  the 
erethism  and  occasional  hallucinations.  The  tremor  is  also  of  cerebral 
origin  probably,  though  this  is  not  yet  certain,  and  the  general  muscular 
weakness  is  not  due  to  the  peripheral  muscles  and  nerves  being  affected, 
but  to  the  alterations  in  the  centres.  As  regards  the  paralysis  sometimes 
observed  in  the  arms  or  legs  in  workers  in  mercury,  Letulle  believes  it  to 
be  caused  by  the  poison  acting  on  the  peripheral  nerves  and  destroying 
the  myeline  sheath.  The  areas  of  partial  anaesthesia  and  the  pains  in 
joints  may  also  prove  to  be  due  to  peripheral  changes.  In  some  cases, 
especially  where  the  tremor  is  marked,  the  reflex  excitability  of  the 
spinal  cord  has  been  found  to  be  exaggerated,  but  it  is  generally  unaf- 
fected. The  muscles  do  not  seem  to  be  acted  on  directly  in  either 
acute  or  chronic  poisoning  in  man,  and  even  when  paralysis  is  de- 
veloped, they  maintain  their  irritability  and  do  not  atrophy.  In  the 
frog  mercury  weakens  the  muscles,  but  only  after  doses  which  are  suf- 
ficient to  paralyze  both  the  central  nervous  system  and  the  heart. 

A  good  deal  of  interest  has  been  manifested  in  the  question  whether 
mercury  affects  the  Nutrition  in  any  way  except  through  its  action  on 
the  alimentary  canal.  Several  authors  have  stated  that  the  urea  is  in- 
creased by  the  use  of  small  doses,  but  the  subject  is  a  very  difficult 
one  to  investigate,  for  when  any  save  the  smallest  doses  are  given,  the 
kidney  and  bowel  are  involved  in  the  effects,  and  the  prolonged  use  of 
mercury  is  restricted  to  experiments  on  animals  and  on  syphilitics. 
There  seems,  however,  good  reason  to  believe  that  very  small  doses  of 
mercury  given  for  some  time  increase  the  nutrition  and  weight  of  ani- 
mals. The  cachexia  of  chronic  poisoning  may  be  due  in  part  to  a 
specific  action  on  the  metabolism,  but  it  is  impossible  to  determine 
this  point,  because  the  alterations  in  the  alimentary  tract  are  in  them- 
selves sufficient  to  cause  such  symptoms.  Meyer  found  that  mercury 
lessened  to  some  extent  the  alkalinity  of  the  blood,  probably  by  the 
formation  of  lactic  acid  in  excess. 

Changes  in  the  Blood  Corpuscles  have  been  observed  under  mercurial 
treatment  in  a  number  of  instances,  but  there  is  as  yet  no  general 
agreement  as  to  wherein  these  consist,  and  it  seems  not  unlikely  that 
the  blood  reaction  in  health  is  different  from  that  in  syphilis  and  that 
it  may  vary  in  the  successive  stages  of  the  disease.  In  health  the  red 
corpuscles  and  the  haemoglobin  are  said  to  be  augmented  at  first  but 
afterwards  diminished,  while  in  syphilis  a  sharp  fall  in  the  amount  of 
haemoglobin  is  succeeded  by  an  increase  to  beyond  that  present  before 
the  treatment.  Kuperwasser  states  that  in  healthy  persons  mercury 
increases  the  number  of  newly  formed  leucocytes  but  that  this  is  more 
than  counterbalanced  by  the  fall  in  the  older  cells ;  in  syphilis  he 
found  fewer  recently  formed  leucocytes  and  more  mature  ones  after 
mercury. 


644  THE  HEAVY  METALS. 

Mercury  has  no  effect  on  the  Temperature  in  itself,  but  when  sto- 
matitis or  skin  eruptions  are  developed,  some  fever  generally  accom- 
panies them,  while  in  collapse  the  temperature  may  fall  several  degrees 
below  the  normal. 

Distribution.  —  After  its  prolonged  use  mercury  is  found  in  almost 
every  organ  of  the  body,  but  larger  quantities  are  found  in  the  kidney 
and  liver  than  elsewhere,  and  it  seems  to  be  stored  in  these  organs 
longer  than  in  any  other.  In  cases  of  acute  poisoning  through  ab- 
sorption from  the  subcutaneous  tissue  or  from  wounded  surfaces,  the 
distribution  is  the  same.  The  statement  that  mercury  is  stored  up  in 
large  quantities  in  the  bones  has  not  been  confirmed  by  the  more  re- 
cent investigators,  but  traces  are  found  here,  as  in  the  muscles,  brain, 
lungs,  intestine  and  spleen. 

Mercury  is  Eliminated  by  almost  all  the  excretory  organs,  but  most 
largely  by  the  intestine  and  kidney.  It  has  been  found  in  small  quan- 
tities in  the  perspiration,  milk,  saliva,  gastric  juice  and  bile,  and  has 
been  shown  to  pass  to  the  foetus  in  utero  through  the  placental  circu- 
lation. The  excretion  begins  within  one  or  two  days  after  absorption, 
but  is  very  slow  and  irregular.  Mercury  has  certainly  been  found  in 
the  urine  six  months  after  its  administration  had  been  stopped,  and 
some  authors  state  that  it  may  be  detected  in  it  for  years  afterwards. 
It  is  open  to  question,  however,  whether  these  last  cases  of  very  pro- 
longed excretion  are  not  to  be  explained  by  the  patients  having  been 
exposed  to  the  fumes  of  mercury  in  the  interim.  At  the  same  time  it 
is  not  impossible  that  pockets  of  mercury  may  be  encapsuled  in  the 
tissues  when  the  insoluble  preparations  are  injected,  exactly  as  a  lead 
bullet  may  be,  and  that  after  a  long  time  some  irritation  such  as  a  blow 
may  again  liberate  it  and  permit  of  its  excretion.  The  elimination 
is  said  to  last  longer  when  the  mercury  is  rubbed  into  the  skin  than 
when  it  is  given  by  the  mouth,  or  when  soluble  preparations  are  in- 
jected hypodermically.  This  is  explained  by  the  drug  passing  more 
slowly  through  the  skin,  which  continues  to  contain  some  of  it  long 
after  the  inunction  treatment  has  ceased.  Mercury  often  disappears 
from  the  urine  for  several  days  or  even  weeks  at  a  time,  and  then  re- 
turns again.  It  is  said  that  more  mercury  is  found  in  the  urine  after 
its  hypodermic  injection  than  after  inunction,  but  even  in  the  most 
favorable  circumstances  only  a  small  proportion  of  that  absorbed  is 
excreted  by  the  kidneys.  In  the  urine  the  mercury  probably  exists 
for  the  most  part  in  the  form  of  a  salt,  although  some  of  it  may  be 
in  organic  combination. 

Mercury  forms  very  poisonous  compounds  with  methyl  and  ethyl,  which 
are  apparently  very  slowly  decomposed  in  the  organism  to  ordinary  forms, 
and  which  have  given  rise  to  fatal  poisoning  in  two  cases,  the  symptoms 
making  their  appearance  only  long  after  the  ingestion.1 

Therapeutic  Uses.  —  The  chief  purpose  for  which  mercury  is  used  in- 
ternally is  the  treatment  of  Syphilis.     Its  curative  effects  in  this  dis- 
1  Hepp,  Arch.  f.  exp.  Path.  u.  Phann.,  xxiii.,  p.  91. 


MERCURY.  645 

ease  can  be  explained  at  present  only  by  supposing  that  it  develops  a 
specific  destructive  action  on  the  syphilitic  virus.  Its  virtues  are 
attested  by  the  great  majority  of  the  medical  profession,  but  a  com- 
paratively small  minority  still  oppose  its  use,  and  some  have  even 
gone  so  far  as  to  assert  that  instead  of  curing  syphilis  it  promotes  the 
development  of  tertiary  symptoms.  Less  extreme  opponents  of  the 
mercurial  treatment  hold  that,  while  the  secondary  symptoms  cer- 
tainly disappear  under  it,  they  are  only  rendered  latent,  and  reappear 
in  course  of  time,  whereas  without  mercury  they  would  have  run 
their  course  in  the  first  instance  and  disappeared.  There  is  no  ques- 
tion that  a  certain  proportion  of  cases  of  syphilis  recover  without  the 
use  of  mercury,  and  indeed  without  the  use  of  any  drug.  In  many 
of  these,  however,  the  course  of  the  disease  can  be  shortened  by  mer- 
cury, and  in  many  others,  in  which  the  symptoms  show  no  signs  of 
abating  under  hygienic  measures,  mercury  causes  a  rapid  and  perma- 
nent improvement.  A  certain  number  of  relapses  undoubtedly  occur 
after  the  mercurial  treatment  has  been  left  off,  but  it  seems  probable 
that  many  of  these  would  not  have  had  even  temporary  relief  without 
mercury.  As  to  the  old  argument  that  tertiary  syphilis  is  caused  by 
the  use  of  mercury  in  the  earlier  stages,  it  has  been  shown  that  tertiary 
syphilis  occurs  without  mercury,  and  that  the  lesions  caused  in  it  are 
entirely  different  from  those  induced  by  this  metal.  The  opponents  of 
mercurial  treatment  frequently  assume  that  it  is  necessarily  followed 
by  cachexia  and  by  all  the  lasting  disorders  which  its  abuse  leads  to. 
At  the  present  time,  however,  mercury  is  administered  in  small  quan~ 
tities,  and  syphilologists  are  agreed  that  it  ought  not  to  be  allowed  to 
induce  any  but  the  earliest  symptoms  of  chronic  poisoning.  To  sum- 
marize the  view  held  by  the  great  majority  of  authorities,  it  may  be 
said  that  mercury  is  of  benefit  in  a  very  large  proportion  of  cases, 
although  it  is  not  essential  to  the  treatment  of  some  favorable  ones, 
and  that  it  is  unable  to  arrest  the  progress  of  the  disease  in  a  certain 
proportion  of  malignant  forms. 

A  question  that  is  still  debated,  and  which,  like  the  other  matters  of 
doubt  concerning  the  mercurial  treatment  of  syphilis,  has  given  rise  to 
an  overwhelming  literature,  is  whether  mercury  ought  to  be  exhibited 
as  soon  as  the  diagnosis  of  primary  syphilis  is  made,  or  whether  the 
advent  of  the  secondary  stage  is  to  be  awaited.  Practice  differs  in  this 
respect,  but  probably  the  majority  of  physicians  do  not  prescribe  mer- 
cury until  some  secondary  symptom  makes  its  appearance,  and  then 
continue  its  administration  until  the  disease  disappears,  or  until  sali- 
vation or  stomatitis  warns  against  its  further  use.  Some  authorities 
recommend  that  mercury  be  continued  for  months  after  the  secondary 
symptoms  have  been  relieved,  in  order  to  prevent  relapse,  but  this  is 
less  rigidly  carried  out  now  than  in  the  earlier  decades  of  last  century, 
In  tertiary  syphilis  mercury  is  generally  considered  inferior  to  the 
iodides,  but  when  the  disease  attacks  any  important  organ,  such  as  the 
brain  or  eye,  mercury  is  more  reliable,  or  both  mercury  and  iodide  may 


646  THE  HEA  VY  METALS. 

be  prescribed  together.  In  hereditary  syphilis  mercury  is  much  more 
efficient  than  iodides. 

Mercury  has  been  used  in  syphilis  in  a  large  number  of  forms,  and 
of  late  years  new  preparations  and  new  methods  of  administration 
have  succeeded  each  other  so  rapidly  that  it  is  impossible  to  discuss 
them  all.  Formerly  mercury  was  given  by  the  mouth  or  by  inunction, 
and  apart  from  the  special  clinics  and  the  syphilologists,  the  internal 
treatment  is  still  the  most  popular  one.  The  preparations  generally 
used  for  internal  administration  are  corrosive  sublimate,  calomel,  or 
the  metallic  preparations  —  blue  pill  and  gray  powder  —  the  last  being 
used  most  widely  in  England.  Calomel  and  the  metallic  preparations 
are,  however,  very  liable  to  induce  diarrhoea,  from  their  being  insoluble 
and  thus  passing  into  the  intestine  before  being  absorbed,  and  opium 
is  therefore  often  prescribed  along  with  them.  Calomel  is  also  credited 
with  causing  salivation  and  stomatitis  more  readily  than  the  other 
preparations,  perhaps  because  it  is  more  difficult  to  gauge  how  much 
of  it  is  absorbed  than  in  the  case  of  the  soluble  perchloride.  Mercury 
administered  by  the  mouth  is  in  all  cases  more  liable  to  derange  the 
digestion  than  when  administered  by  other  channels.  Accordingly, 
inunction  was  introduced  to  avoid  the  disturbance  of  the  stomach  and 
intestine  caused  by  the  local  action  of  the  mercury,  while  that  due  to 
its  excretion  along  the  alimentary  tract  remained  unchanged.  By  this 
method  the  mercury  is  rubbed  into  the  skin  in  the  form  of  ointment  ; 
that  most  frequently  used  consists  of  metallic  mercury  suspended  in  a 
state  of  fine  division  in  lard,  but  others  have  been  suggested,  such  as 
the  oleate  of  mercury,  the  ointment  of  the  yellow  oxide,  and  mercury 
soaps.  The  first  is  less  irritant,  however,  and  has  entirely  supplanted 
the  others,  which  never  enjoyed  a  very  wide  popularity.  The  action 
of  mercury  is  somewhat  more  slowly  elicited  by  this  method  than  when 
it  is  administered  internally,  but  lasts  longer,  and  the  digestion  is  less 
liable  to  be  disturbed.  The  mercury  is  absorbed  in  the  form  of  a 
proteid  combination  from  the  gland  ducts,  and  probably  a  small  quan- 
tity is  inhaled  by  the  lungs  as  vapor.  The  objection  to  the  method  is 
that  it  is  inconvenient  and  uncleanly,  and  that  it  is  even  less  possible 
to  estimate  the  amount  of  mercury  actually  absorbed  than  when  it  is 
given  by  the  mouth.  One  case  of  fatal  poisoning  has  been  recorded 
from  the  ointment  being  applied  to  sore  hands.  Instead  of  mercury 
ointment  being  rubbed  into  the  skin,  one  of  the  plasters  or  lint  con- 
taining mercurial  ointment  (Weylander)  may  be  applied  to  it,  permit- 
ting of  the  continuous  absorption  of  small  quantities  by  the  skin  and 
by  inhalation  of  the  vapor. 

In  1867,  Lewin  introduced  the  hypodermic  or  intramuscular  injection 
of  a  dilute  solution  of  corrosive  sublimate,  and  this  has  been  very 
widely  practised  of  late  years,  and  with  great  success.  The  advantages 
of  the  method  are  the  avoidance  of  digestive  disturbance,  which  is 
shared  by  the  inunction  method,  its  cleanliness,  the  more  accurate  esti- 
mation of  the  amount  of  mercury  actually  administered,  and  the  greater 


MERCURY.  647 

rapidity  of  action.  Its  chief  disadvantage  is  the  pain  caused  by  the 
injection,  which  has  to  be  repeated  daily  ;  some  inflammation  and 
swelling  follow  immediately,  but  no  suppuration,  when  ordinary  care 
is  taken  ;  but  the  pain  is  very  intense  and  persistent  and  many  patients 
refuse  to  continue  the  treatment.  Salivation  is  said  to  follow  this 
method  more  seldom  than  any  other,  and  relief  from  the  secondary 
syphilitic  symptoms  is  gained  sooner.  Lewin  continues  to  use  the  per- 
chlpride  solution  and  prefers  it  to  any  of  the  modifications ;  others 
have  added  morphine,  or,  more  recently,  cocaine,  in  order  to  lessen  the 
pain,  but  this  is  to  be  deprecated  from  the  danger  of  the  habit  being 
formed.  The  addition  of  chloride  of  sodium  tends  to  prevent  the  pre- 
cipitation of  proteids  by  the  perchloride,  and  a  solution  of  perchloride 
of  mercury,  with  ten  times  its  weight  of  common  salt  or  of  urea  has 
therefore  been  advocated,  while  others  have  used  the  peptonate  or  the 
albuminate  of  mercury  dissolved  in  salt  solution.  Mercury  has  a  strong 
affinity  for  the  amido-group,  and  in  combination  with  it  has  little  ten- 
dency to  precipitate  proteids,  and  this  has  led  to  the  use  of  preparations 
of  mercury  with  the  amido-acids,  such  as  glycocoll,  formamide  or  suc- 
cinimide.  Many  of  these  methods  are  said  to  lessen  the  pain  of  hypo- 
dermic injection,  but  do  not  remove  it  entirely,  probably  because  the 
various  compounds  undergo  some  dissociation  in  the  tissues,  and  the 
free  mercury  ion  causes  the  same  irritation  as  if  the  perchloride  had 
been  injected. 

Instead  of  the  soluble  preparations  of  mercury,  which  necessitate 
the  painful  injections  being  repeated  daily,  insoluble  salts  have  been 
injected,  with  the  idea  that  these  being  slowly  dissolved  and  absorbed 
from  the  seat  of  injection,  a  quantity  sufficient  for  several  days  may 
thus  be  given  at  one  time.  Instead  of  injecting  these  insoluble  prep- 
arations hypodermieally,  they  are  often  thrown  into  the  muscular  tissue. 
According  to  the  advocates  of  this  method,  it  causes  less  immediate  pain 
than  perchloride  injections,  but,  as  solution  takes  place,  and  the  mer- 
cury attacks  the  tissues,  the  part  becomes  extremely  painful,  swollen, 
and  inflamed.  Suppuration  and  even  gangrene  have  been  developed 
in  a  very  considerable  number  of  cases,  and  in  others  severe  or  fatal 
mercury  poisoning  has  been  observed.  The  advantages  of  the  method 
are  that  the  physician  has  not  to  visit  the  patient  every  day,  and  that 
the  injection  need  only  be  made  once,  or  at  most  twice  a  week.  On 
the  other  hand,  the  local  lesions  are  often  very  severe,  and  the  amount 
of  mercury  absorbed  cannot  be  controlled  in  any  way.  It  has  the  ad- 
vantage over  the  administration  per  os  that  the  digestion  is  not  so 
liable  to  be  interfered  with,  but,  as  has  been  said,  the  danger  and 
pain  are  very  much  greater.  Many  authorities  therefore  deprecate 
the  use  of  these  insoluble  preparations  by  injection,  but  a  considerable 
number  of  syphilologists  still  persist  in  their  use,  and  new  preparations 
have  been  introduced  for  this  purpose  in  large  numbers.  Those  most 
commonly  used  are  calomel  in  salt  solution  or  in  liquid  paraffin,  me- 
tallic mercury  in  very  fine  division  suspended  in  liquid  paraffin,  the 


648  THE  HEA  VY  METALS. 

salicylate,  benzoate,  and  the  thymol-acetate.  The  oxides  have  also 
been  proposed  and  many  other  preparations  have  received  a  trial  by 
this  method. 

Other  methods  of  introducing  mercury  into  the  tissues  are  more  rarely 
employed.  The  intravenous  injection  of  the  perchloride  has  been  suggested 
for  the  treatment  of  cases  in  which  there  is  urgent  haste,  but  has  rarely  been 
carried  out,  and  is  likely  to  prove  dangerous  from  the  formation  of  emboli, 
and  also  from  the  effects  of  mercury  on  the  heart  when  thus  applied. 

Suppositories  of  mercury  have  been  used  to  some  extent,  and  are  said  to 
disturb  the  digestion  less  than  the  administration  per  os. 

Mercury  fumigations  have  also  been  practised  to  a  limited  extent,  the 
vapor  of  mercury  being  freed  by  heating  calomel  or  the  sulphide.  The  pa- 
tient sits  in  a  wooden  tent  up  to  his  neck  and  the  mercury  deposited  on  the 
skin  is  absorbed.  The  method  is  very  cumbrous,  and  the  quantity  of  mer- 
cury taken  up  cannot  be  controlled. 

Mercury  was  recommended  by  Hamilton  in  the  beginning  of  last 
century  in  the  treatment  of  Acute  Febrile  Affections,  and  the  greatest 
abuse  unquestionably  prevailed  in  the  earlier  decades.  Later  its 
sphere  of  usefulness  was  restricted  to  the  treatment  of  inflammation  of 
the  serous  membranes — pleurisy,  meningitis,  pericarditis,  peritonitis  — 
and  many  physicians  still  maintain  that  it  checks  the  effusion  and  pro- 
motes the  healing  of  these  diseases.  Others  deny  that  mercury  pos- 
sesses any  virtues  in  these  cases,  and  its  use  is  undoubtedly  becoming 
more  limited ;  in  acute  iritis  it  is  still  used  almost  universally.  In 
these  cases  it  is  always  administered  by  the  mouth  in  the  form  of 
calomel,  blue  pill  or  gray  powder. 

As  a  Purgative  mercury  is  very  frequently  prescribed  in  "  bilious- 
ness," and  in  putrefactive  diarrhoea.  It  acts  partly  from  its  antiseptic 
power,  but  mainly  by  removing  the  putrefying  contents  from  the  in- 
testine ;  calomel,  blue  pill,  or  gray  powder  is  usually  employed  with 
or  without  the  addition  of  a  vegetable  purge. 

Calomel  has  proved  of  only  doubtful  value  as  an  intestinal  antisep- 
tic in  typhoid  fever,  dysentery  and  other  similar  conditions. 

Calomel  and  other  mercurials  have  long  been  known  to  be  of  value 
in  cases  of  Dropsy,  but  Jendrassik  deserves  the  credit  of  having  re- 
vived their  employment  as  diuretics,  for  this  use  of  mercury  had  fallen 
into  oblivion.  The  best  preparation  is  calomel,  given  in  0.2  G.  (3 
grs.)  doses  three  times  a  day  or  in  0.1  G.  (2  grs.)  doses  5-10  times  a 
day.  It  is  of  great  value  in  certain  cases  of  cardiac  dropsy,  but  is 
less  reliable  in  the  accumulations  of  fluid  met  with  in  hepatic  or  renal 
disease,  although  here  too  its  administration  is  sometimes  followed  by 
the  rapid  excretion  of  the  fluid.  It  does  not  seem  to  be  contraindi- 
cated  in  chronic  nephritis,  although  its  action  has  to  be  carefully  con- 
trolled. It  has  no  effect  in  removing  the  exudations  of  acute  inflam- 
mation such  as  pleurisy. 

Mercury  is  used  Externally  as  an  Antiseptic  wash  in  surgical  opera- 
tions, chiefly  in  the  form  of  the  perchloride,  but  also  as  the  cyanide 


MERCURY.  649 

and  oxycyanide.  It  is  irritant  to  wounds,  however,  and  is  liable  to  be 
absorbed  when  applied  to  large  surfaces,  and  several  cases  of  fatal 
poisoning  have  been  recorded  from  the  use  of  even  the  most  dilute 
solutions  of  corrosive  sublimate  to  wash  out  the  uterus  and  vagina. 
These  preparations,  more  especially  the  perchloride,  have  also  the  dis- 
advantage of  attacking  steel  instruments. 

Numerous  ointments  have  been  applied  externally  in  the  treatment 
of  Skin  Diseases,  particularly  those  of  a  parasitic  nature,  such  as  itch, 
and  in  condylomata,  ulcers  and  skin  diseases  of  syphilitic  origin. 
These  preparations  combine  an  antiseptic  with  a  more  or  less  irritant 
action,  and  unlike  carbolic  acid  and  its  allies,  are  equally  powerful 
antiseptics  in  ointments  and  in  water.  The  least  irritant  of  the  phar- 
macopoaial  ointments  is  the  mercury  ointment ;  then  the  oleate,  yel- 
low oxide,  red  oxide,  and  ammoniated  mercury  follow  in  order,  while 
citrine  ointment  is  much  more  irritant  and  corrosive.  Other  external 
applications  are  the  plasters  and  the  black  and  yellow  wash.  Oint- 
ments containing  calomel,  corrosive  sublimate,  and  other  preparations 
are  sometimes  prescribed,  or  calomel  may  be  used  as  a  dusting  powder 
in  syphilitic  ulcers.  The  mercury  ointments  are  frequently  applied  to 
the  eye,  the  milder  ones  as  antiseptics  and  slight  irritants,  citrine  oint- 
ment to  destroy  granulations. 

Mercurial  ointments  are  sometimes  employed  to  promote  the  absorp- 
tion of  subcutaneous  effusions  and  to  reduce  swellings.  They  are  not 
superior  to  other  irritants  for  this  purpose,  however,  and  have  the  dis- 
advantage of  permitting  the  absorption  of  a  dangerous  poison. 

The  nitrate  of  mercury  and  its  ointment  (citrine)  are  sometimes  used 
as  caustics  for  application  to  the  os  uteri,  condylomata  and  elsewhere. 

Mercury  treatment  is  Contraindicated,  or  requires  special  caution  in 
cases  of  profound  cachexia,  weakness,  or  anaemia,  unless  these  arise 
from  syphilis.  Where  the  digestion  is  weak,  it  ought  to  be  avoided  if 
possible,  and  in  cases  of  tuberculosis  there  is  always  the  danger  that 
the  disturbance  of  the  digestion  may  accelerate  the  course  of  the  dis- 
ease. In  severe  nephritis  it  is  also  to  be  used  with  caution,  although 
it  is  beneficial  in  some  cases,  and  although  some  authorities  deny  that 
it  is  injurious  even  when  it  has  no  diuretic  action.  In  pregnancy  mer- 
cury is  not  absolutely  contraindicated,  at  any  rate  up  to  the  sixth 
month.  Later  it  is  liable  to  injure  the  patient  by  its  action  on  the  di- 
gestion, and  in  some  cases  has  induced  abortion  ;  the  child  may  also 
suffer  from  mercurial  poisoning.  Mercurial  ointments  or  dusting 
powders  have  to  be  used  with  care  when  iodides  are  being  administered 
internally,  as  the  iodide  excreted  forms  the  iodide  of  mercury,  and 
this  may  cause  violent  corrosion.  Thus  in  the  eye,  severe  effects  have 
been  induced  by  the  application  of  calomel  to  the  cornea  while  iodide 
was  being  given. 

In  cases  of  Acute  Corrosive  Poisoning,  the  indications  are  the  evac- 
uation of  the  stomach,  preferably  by  the  stomach  tube.  Tannic  acid, 
or  eggs,  milk  and  other  albuminous  substances  may  be  given  to  pre- 


650  THE  HEAVY  METALS. 

cipitate  the  metal  and  protect  the  mucous  membrane.     The  treatment 
of  the  later  symptoms  is  the  same  as  that  of  the  chronic  form. 

In  Chronic  Poisoning  the  salivation  and  stomatitis  are  treated  by  the 
use  of  chlorate  of  potash  solution  as  a  mouth  wash,  and  its  free  applica- 
tion during  mercurial  'treatment,  along  with  careful  brushing  of  the 
teeth,  is  believed  by  most  physicians  to  hinder  the  onset  of  the 
symptoms.  Tannic  acid  solution  is  also  recommended  as  a  mouth  wash. 
The  diarrhoea  may  be  treated  with  opium,  the  other  symptoms  on 
general  principles.  In  any  case  the  drug  ought  to  be  abandoned,  or 
the  dose  much  reduced  as  soon  as  the  salivation  becomes  marked.  In 
chronic  poisoning  not  arising  from  the  therapeutic  use  of  the  drug, 
iodide  of  potassium  is  generally  prescribed,  although  its  utility  has  not 
yet  been  placed  beyond  question.  Sulphur  baths,  and  hot  baths 
without  sulphur  are  also  recommended. 

PREPARATIONS. 

HYDRARGYRI  CHLORIDUM  CORROSIVUM  (U.  S.  P.),  HYDRARGYRI  PER- 
CHLORIDUM  (B.  P.),  CORROSIVE  SUBLIMATE  (HgCl2),  forms  heavy,  colorless 
crystals,  without  odor,  but  possessing  an  acrid,  metallic  taste,  soluble  in  16 
parts  of  cold  water,  in  2  parts  of  boiling  water,  in  3  parts  of  alcohol,  and 
in  4  parts  of  ether. 

LIQUOR  HYDRARGYRI  PERCHLORIDI  (B.  P.)  contains  ^  gr.  in  a  fluid 
dr.,  £-1  fl.  dr. 

Corrosive  sublimate  is  one  of  the  most  irritant  preparations,  and  is  rapidly 
absorbed.  It  is  used  internally  in  syphilis,  0.002-0.02  G.  (yV-i  grO/  in  one 
per  cent,  solution  and  is  also  injected  hypodermically  in  0.6  per  cent,  solu- 
tion, 2  c.c.  (30  mins.)  daily.  This  solution  is  often  made  up  with  6  per  cent, 
of  sodium  chloride  or  urea.  Perchloride  of  mercury  is  less  liable  to  induce 
salivation,  but  disturbs  the  digestion  more  than  other  preparations  when 
given  internally,  while  its  hypodermic  injection  is  exceedingly  painful.  It 
has  induced  fatal  poisoning  in  the  dose  of  0.18  G.  (3  grs.),  taken  by  the 
mouth,  but  in  other  cases  much  larger  quantities  have  been  recovered  from. 
It  is  stated  that  opium  eaters  can  take  enormous  quantities  without  evil 
effects. 

It  is  used  extensively  in  surgery  as  an  antiseptic  solution  (1  in  2,000-4,000), 
to  disinfect  the  hands,  wounds,  etc.,  but  is  irritant  to  delicate  tissues,  such 
as  the  peritoneum,  and  corrodes  steel  instruments.  It  is  also  used  in  the 
form  of  a  soap  and  to  impregnate  bandages,  cotton-wool,  gauze,  catgut 
and  silk.  It  preserves  its  antiseptic  action  in  oils  and  ointments.  It  has 
been  used  to  a  limited  extent  in  skin  diseases  in  solution,  in  baths,  or  in 
ointment,  as  a  local  application  in  diphtheria,  and  as  an  intestinal  antiseptic 
in  putrefactive  diarrhrea,  typhoid  fever  and  cholera. 

The  albuminate  and  peptonate  of  mercury  are  formed  by  precipitating  a 
solution  of  egg  albumin  or  of  meat  peptone  with  a  five  per  cent,  solution  of 
corrosive  sublimate.  The  precipitate  is  collected,  washed  and  dissolved  in 
20  per  cent,  chloride  of  sodium  solution.  It  was  hoped  that  these  prepara- 
tions would  not  cause  irritation  and  pain  when  injected  subcutaneously,  but 
this  anticipation  has  not  been  fulfilled  and  they  have  fallen  into  almost 
complete  disuse.  They  are  not  official. 

Hydrargyri  Cyanidum,  mercuric  cyanide  (Hg(CN)2),  colorless  crystals,  without 
odor  but  with  a  bitter,  metallic  taste,  soluble  in  about  12  parts  of  water,  in  15 
parts  of  alcohol.  The  cyanide  resembles  the  perchloride  in  its  action  and  has 
been  used  hypodermically  in  syphilis.  As  a  surgical  antiseptic  it  is  equal  to 

1  The  B.  P.  gives  as  the  dose  or  corrosive  sublimate  and  the  red  iodide,  g^-ie  £r- 


MERCURY.  651 

corrosive  sublimate  and  attacks  steel  instruments  less.     Dose,   as  of  corrosive 
sublimate. 

The  oxy cyanide  of  mercury.  (Hg2O(CN)2)  is  also  used  to  form  an  antiseptic 
lotion  in  surgery.  The  double  cyanide  of  mercury  and  zinc  has  been  recom- 
mended by  Lister  for  this  purpose. 

HYDRARGYRI  IODIDUM  KUBBUM  (U.  S.  P.,  B.  P.),  red  iodide.of  mercury, 
biniodide  of  mercury  (HgI2),  a  scarlet-red,  amorphous  powder,  tasteless  and 
odorless,  almost  insoluble  in  water,  but  soluble  in  solution  of  iodide  of  po- 
tassium. 0.005-0.02  G.  GV-i  gr.),  (B.  P.sVrV  gr-)- 

This  preparation  is  very  seldom  prescribed  as  such,  but  is  frequently 
formed  by  prescribing  a  mixture  of  corrosive  sublimate  and  potassic  iodide, 
when  the  iodide  of  mercury  is  formed  and  is  kept  in  solution  by  the  excess  of 
the  iodide  of  potassium.  This  prescription  is  often  indicated  in  the  transi- 
tional period  between  secondary  and  tertiary  syphilis,  and  even  when  the 
tertiary  symptoms  are  fully  developed. 

Liquor  Arseni  et  Hydrargyri  lodidi  (U.  S.  P.,  B.  P.),  Donovan's  solution, 
contains  one  per  cent,  each  of  arsenic  iodide  and  red  mercuric  iodide.  Used 
as  a  tonic  in  syphilitic  and  other  cases.  0.3-1.3  c.c.  (5-20  mins.). 

Unguentum  Hydrargyri  lodidi  Rubri  (B.  P.),  4  per  cent. 

HYDRARGYRI  CHLORIDUM  MITE  (U.  S.  P.),  HYDRARGYRI  SUBCHLORIDUM 
(B.  P.),  mild  inercurous  chloride,  CALOMEL  (Hg2Cl2),  a  heavy  white  powder 
without  odor  or  taste,  insoluble  in  water,  alcohol  and  ether.  0.03-0.3  G. 
(£-5  grs.)  in  powder,  less  suitably  in  pill  form. 

Pilulse  Antimonii  Composita  (U.  S.  P.),  Pilula  Hydrargyri  Subchloridi  Com' 
posita  (B.  P.).  See  Antimony,  page  633. 

Unguentum  Hydrargyri  Subchloridi  (B.  P.),  10  per  cent. 

Calomel  is  contained  in  the  compound  cathartic  pill  U.  S.  P.  (p.  105). 

Calomel  is  used  in  syphilis  (dose,  0.05  G.  (1  gr.)  thrice  daily),  but  is  credited 
with  being  more  liable  to  induce  salivation  than  other  preparations,  and  its 
purgative  action  often  has  to  be  counteracted  by  opium.  A  suspension  of  1 
part  calomel  in  20  parts  of  10  per  cent,  salt  solution  or  of  liquid  paraffin  is  often 
injected  into  the  buttock  in  syphilis  ;  the  dose  of  calomel  by  this  method  is 
0.05-0.1  G.  (1-1?  grs.)  once  a  week.  As  a  purge  and  intestinal  disinfectant  it  is 
of  value  in  biliousness,  and  in  the  diarrhrea  of  putrefaction,  less  so  in  diseases  in 
which  the  intestinal  wall  is  the  site  of  infection,  as  in  typhoid  fever  and  cholera. 
Calomel  causes  less  irritation  and  colic  than  most  other  purges,  and  small  doses 
are  followed  by  only  one  evacuation.  It  may  therefore  be  given  where  pre- 
existing irritation  of  the  intestine  contraindicates  the  use  of  most  other  pur- 
gatives. Calomel  is  often  advised  in  hepatic  affections,  but  it  is  a  question 
whether  it  has  any  effect  here  except  as  a  purge.  It  is  of  great  value  in  some 
forms  of  dropsy,  especially  those  of  cardiac  origin,  in  which  it  is  administered 
in  0.2  G.  (3  gr.)  doses  thrice  a  day  for  2-4  days,  and  is  stopped  as  soon  as 
the  diuresis  sets  in.  The  treatment  may  be  repeated  if  the  dropsy  returns. 
Alkalies  are  often  added  to  calomel  prescriptions  on  the  ground  that  in  this 
way  there  is  less  danger  of  the  calomel  being  changed  to  corrosive  sublimate 
in  the  stomach.  For  the  same  reason,  acids  are  often  avoided  for  some  time 
after  calomel  is  taken.  As  a  matter  of  fact  these  fears  are  quite  groundless, 
as  calomel  is  not  changed  to  the  perchloride  in  the  stomach  and  it  is  there- 
fore quite  unnecessary  to  add  alkalies  to  calomel. 

Calomel  has  been  used  externally  as  a  dusting  powder  for  syphilitic 
condylomata,  as  a  slight  irritant  to  the  cornea  and  as  an  ointment  in  pruritus 
and  other  skin  diseases. 

Hydrargyri  lodidum  Flavum  (U.  &.  P.),  yellow  or  green  iodide  of  mercury 
(Hg2I2),  a  bright  yellow  amorphous  powder,  tasteless  and  odorless,  insoluble 
in  water,  alcohol  or  ether. 

It  has  been  used  in  syphilis,  with  the  idea  of  uniting  the  virtues  of  the 
iodides  and  of  mercury.     But  the  quantity  of  iodide  is  altogether  inadequate 
0.05-0.2  G.  (1-3  grs.). 


652  THE  HEAVY  METALS. 

HYDRARGYRUM  CUM  GRETA  (U.  S.  P.,  B.  P.),  mercury  with  chalk,  GRAY 
POWDER,  is  formed  by  rubbing  up  metallic  mercury  with  chalk  and  honey 
(U.  S.  P.)  until  the  mercury  is  divided  into  very  fine  globules,  each  encased 
in  chalk.  It  forms  a  light-gray,  somewhat  damp  powder,  without  odor  and 
with  a  sweetish  taste  from  the  honey.  The  mercury  (38  per  cent.  U.  S.  P. , 
33  per  cent.  B.  P.),  remains  in  the  metallic  state,  very  little  oxide  being 
formed.  It  is  insoluble  in  water,  alcohol  and  ether,  and  is  always  prescribed 
in  powder  form.  0.1-0.5  G.  (2-8  grs.). 

MASSA  HYDRARGYRI  (U.  S.  P.),  mass  of  mercury,  BLUE  MASS,  BLUE  PILL, 
is  formed  from  metallic  mercury  by  rubbing  it  with  Mel  Rosse,  glycerin,  al- 
thaea and  liquorice  until  the  globules  are  invisible  under  a  lens  magnifying 
ten  diameters.  The  blue  mass  contains  about  33  per  cent,  of  mercury  almost 
entirely  in  the  metallic  form.  It  is  of  the  consistency  of  pills  and  is  always 
prescribed  in  this  form.  0.2-0.5  G.  (3-8  grs.). 

PILULA  HYDRARGYRI,  BLUE  PILL,  the  corresponding  B.  P.  preparation, 
is  made  up  with  confection  of  roses  and  liquorice  by  rubbing  them  with 
metallic  mercury  until  the  glolbules  are  no  longer  visible.  4-8  grs. 

These  preparations  are  very  largely  used  as  mild  mercurial  purgatives, 
the  blue  pill  being  frequently  reinforced  by  the  addition  of  one  of  the  vege- 
table purges.  The  gray  powder  is  especially  adapted  for  children,  and  is  of 
value  in  summer  diarrhoea  and  other  similar  conditions.  Blue  pill  is  often 
given  in  cardiac  dropsy  along  with  squills  or  digitalis,  but  has  proved  inferior 
to  calomel  as  a  diuretic.  Gray  powder  is  held  by  some  authorities  to  be  the 
best  form  for  the  internal  treatment  of  syphilis,  and  is  given  in  doses  of  0.05 
G.  (1  gr.)  3  to  5  times  a  day  ;  if  necessary,  opium  may  be  given  to  prevent 
purging.  The  blue  pill  may  also  be  used  in  syphilis  and  is  less  liable  to  purge. 

UNGUENTUM  HYDRARGYRI  (U.  S.  P.,  B.  P.),  mercurial  ointment,  BLUE 
OINTMENT,  is  formed  by  triturating  metallic  mercury  with  lard  and  suet  and 
oleate  of  mercury  until  the  globules  are  invisible  when  magnified  ten  diam- 
eters. The  ointment  contains  about  one  half  its  weight  of  metallic  mercury 
along  with  a  small  proportion  of  oleate. 

Unguentum  Hydrargyri  Compositum  (B.  P.)  contains  camphor  and  is  some- 
what weaker  than  blue  ointment. 

Unguentum  Hydrargyri  Dilutum  (U.  S.  P.)  contains  2  parts  of  mercurial 
ointment  with  1  part  of  petrolate. 

The  famous  blue  ointment  is  used  largely  in  many  forms  of  skin  diseases, 
especially  in  those  of  syphilitic  origin,  and  was  formerly  the  ordinary  treat- 
ment for  scabies,  in  which,  however,  it  has  been  supplanted  by  balsam  of  Peru 
and  other  remedies,  though  it  is  still  used  occasionally  to  destroy  pediculi. 
The  most  important  purpose  for  which  blue  ointment  is  applied  at  the  pres- 
ent time  is  the  treatment  of  syphilis  by  inunction.  For  this  purpose  2-4  G. 
(£-1  dr.)  is  rubbed  in  daily  in  different  parts  of  the  body,  in  order  to  avoid 
the  irritation  induced  by  applying  it  repeatedly  to  one  spot.  A  warm  bath 
is  taken  first,  and  the  patient  then  rubs  in  the  ointment  on  the  inside  of 
the  thighs,  next  day  on  the  inside  of  the  arms,  on  the  following  days  on 
the  forearms,  legs,  abdomen  and  back,  returning  to  the  thighs  on  the  seventh 
day  and  repeating  the  series.  The  treatment  is  continued  for  a  fortnight  or 
three  weeks.  This  method  has  the  advantage  that  the  digestion  is  less  af- 
fected than  when  the  drug  is  given  internally,  but  on  the  other  hand,  the  mer- 
cury is  more  slowly  absorbed  than  by  other  methods  ;  and  no  estimate  of  the 
quantity  really  taken  up  can  be  formed,  as,  although  the  patient  is  directed 
to  rub  it  in  until  the  whole  disappears,  the  instructions  may  be  imperfectly 
carried  out.  Salivation  is  not  so  readily*  produced  as  by  the  administration 
per  os,  but  when  it  occurs,  it  lasts  longer  and  may  become  severe.  One  case 
of  fatal  poisoning  has  been  recorded  from  the  application  of  the  ointment,  but 
in  this  case  the  skin  appears  to  have  been  broken.  Skin  rashes  are  more  fre- 
quent from  inunction  than  from  any  other  method  of  application,  and  finally, 


MERCURY.  653 

the  method  is  extremely  inconvenient  and  dirty.  The  patient  ought  to  carry 
out  the  inunction  himself,  for  any  other  person  doing  so  may  acquire  chronic 
poisoning  from  absorption  through  the  hands,  and  eveu  if  this  is  prevented 
by  the  use  of  gloves  of  India-rubber  or  oiled  bladder,  some  mercury  may  be 
absorbed  by  the  lungs.  In  children  the  ointment  is  often  applied  by  spread- 
ing it  on  a  bandage,  which  is  then  applied  around  the  waist.  In  skin  disease 
and  in  very  hirsute  individuals,  the  inunction  treatment  is  impossible. 

Oleum  Cinereum,  or  gray  oil  (not  official),  is  a  suspension  of  metallic  mercury 
in  liquid  paraffin  or  in  lanolin  and  oil,  and  is  used  in  syphilis  by  intramuscular 
injection.  It  often  is  made  up  to  contain  20  per  cent,  of  mercury,  and  the  dose 
is  then  2-3  c.c.  once  a  week. 

Olealum  Hydrargyri  (U.  S.  P.),  Hydrargyri  Oleas  (B.  P.),  oleate  of  mercury, 
has  been  used  for  the  same  purposes  as  mercury  ointment,  but  is  somewhat 
more  irritant  and  possesses  no  compensating  virtues. 

Unguentum  Hydrargyri  Oleatis  (B.  P.),  1  part  in  4. 

Emplastrum  Hydrargyri  (U.  S.  P.,  B.  P.),  mercury  plaster,  is  formed  in  the 
same  way  as  the  ointment  by  the  trituration  of  metallic  mercury. 

Emplastrum  Ammoniaci  cum  Hydrargyro  (B.  P.)  is  similarly  formed,  but  con- 
tains less  mercury  and  a  large  quantity  of  a  gum- resin  (ammoniac). 

These  plasters  are  sometimes  applied  to  chancres  and  to  syphilitic  ulcers, 
and  mercury  plaster  has  been  applied  instead  of  the  ointment  as  a  treatment 
of  syphilis. 

Linimentum  Hydrargyri  (B.  P.). 

HYDRARGYRI  OXIDUM  FLAVUM  (U.  S.  P.,  B.  P.),  yellow  mercuric  oxide. 

HYDRARGYRI  OXIDUM  EUBRUM  (U.  S.  P.,  B.  P.),  red  mercuric  oxide. 

UNGUENTUM  HYDRARGYRI  OXIDI  FLAVI  (U.  S.  P.  10  per  cent.,  B.  P.  2 
per  cent.). 

UNGUENTUM  HYDRARGYRI  OXIDI  EUBRI  (U.  S.  P.,  B.  P.),  10  per  cent. 

The  two  oxides  are  identical  in  constitution  (HgO),  but  the  yellow  is 
obtained  by  precipitation  from  the  perchloride,  the  red  by  oxidation  of  the 
metal  by  means  of  nitric  acid.  The  red  is  crystalline,  the  yellow  amorphous, 
and  both  are  practically  insoluble  in  water  and  alcohol,  but  are  soluble  in 
acids.  The  red  oxide  is  more  irritant  than  the  yellow  on  account  of  its 
crystalline  form,  and  perhaps  also  because  it  often  contains  some  nitrate. 
The  yellow  oxide  is  used  in  ointment  in  various  diseases  of  the  eye,  and 
both  are  employed  as  applications  to  syphilitic  sores,  condylomata,  and 
chancres,  although  the  red  is  often  preferred  for  this  purpose.  They  have 
also  been  proposed  for  hypodermic  injection  suspended  in  water. 

Two  famous  preparations  of  mercury  are  the  black  and  the  yellow  wash, 
the  former  prepared  from  calomel,  the  latter  from  corrosive  sublimate  by  the 
action  of  lime  water.  The  black  wash,  Lotio  Hydrargyri  Nigra  (B.  P.),  con- 
tains mercurous  oxide  (Hg2O),  the  yellow,  Lotio  Hydrargyri  Flava  (B.  P.), 
mercuric  oxide  (HgO).  The  oxides  are  in  both  cases  insoluble  and  the 
lotions  have  to  be  shaken  before  application.  They  are  used  in  syphilitic 
lesions  as  local  remedies. 

Hydrargyrum  Ammoniatum  (U.  S.  P.,  B.  P.),  mercuric  ammonium  chloride, 
white  precipitate  (XH2HgCl),  is  formed  by  precipitating  corrosive  sublimate 
with  ammonia,  and  is  a  white,  amorphous  powder,  without  odor  and  with 
an  earthy,  metallic  taste,  almost  insoluble  in  water  and  alcohol. 

Unguentum  Hydrargyri  Ammoniati  (U.  S.  P.,  B.  P.),  10  per  cent. 

The  white  precipitate  is  not  used  internally,  and  is  more  irritant  than  the 
oxides.  The  ointment  is  occasionally  applied  in  skin  diseases  and  to  destroy 
parasites. 

Liquor  Hydrargyri  Nitratis  (U.  S.  P.,  B.  P.),  solution  of  mercuric  nitrate, 
contains  about  60  per  cent,  of  the  nitrate  (Hg(NO3)2)  along  with  about  11 
per  cent,  of  free  nitric  acid.  It  is  a  powerfully  corrosive  fluid  which  is  used 
to  cauterize  the  os  uteri,  cancers  or  condylomata.  Symptoms  of  mercury 
poisoning  have  arisen  from  its  application  to  the  os  uteri. 


654  THE  HEAVY  METALS. 

UNGUENTUM  HYDRARGYRI  NITRATIS  (U.  S.  P.,  B.  P.),  citrine  ointment, 
is  used,  diluted  with  oil  or  lard,  in  conjunctivitis,  and  also  as  an  application 
to  syphilitic  sores  and  gangrenous  ulcers. 

Unguentum  Hydrargyri  Citratis  Dilutum  (B.  P.). 

Hydrargyrum  (U.  S.  P.,  B.  P.),  metallic  mercury,  is  not  used  in  thera- 
peutics at  the  present  time.  It  was  formerly  employed  in  cases  of  intestinal 
obstruction  in  large  quantities  (up  to  a  pound  or  more)  in  order  to  drag  the 
intestines  into  place  by  its  weight.  As  a  general  rule  no  symptoms  of  poison- 
ing occurred,  the  mercury  being  voided  unchanged  and  unabsorbed,  but  in 
some  cases  salivation  followed  its  use. 

A  large  number  of  new  preparations  of  mercury  have  been  introduced  of 
late  years  and  have  received  a  more  or  less  extensive  trial,  but  have  seldom 
been  found  to  be  superior  to  the  older  forms.  Among  these  may  be  mentioned 
the  tannate,  which  was  introduced  in  the  hope  that  it  would  cause  less  pur- 
gation than  calomel,  and  might  therefore  be  better  adapted  for  the  treatment 
of  syphilis.  0.1-0.3  G.  (2-5  grs.)  in  powder.  The  carbolate,  salicylate  (either 
neutral  or  basic),  benzoate,  sozoiodolate,  thymol-acetate  and  many  other  similar 
compounds  have  been  used  instead  of  calomel  for  hypodermic  or  intramus- 
cular injection,  have  each  in  succession  been  blazoned  forth  as  the  best 
preparation,  and  will  probably  be  forgotten  in  the  course  of  a  few  years. 
Several  amido  acid  salts  of  mercury  such  as  the  formamide,  the  amido-pro- 
pionate  (alanin  mercury)  and  the  succinimide  have  been  proposed  as  substi- 
tutes for  corrosive  sublimate  in  hypodermic  injection.  It  was  believed  that 
the  affinity  of  mercury  for  nitrogen  being  satisfied  in  these  compounds,  it 
would  attack  the  proteids  less,  and  as  a  matter  of  fact,  the  injections  are 
said  to  be  less  painful  than  those  of  corrosive  sublimate.  Dreser  has  recently 
proposed  mercuric-potassic  hyposulphite,  because  the  mercury  is  apparently 
contained  in  it  in  a  form  which  does  not  admit  of  its  dissociation.  Colloid 
mercury  has  been  suggested  for  inunction  instead  of  the  blue  ointment. 

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IRON.  655 

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III.     IRON. 

Iron  differs  from  the  other  heavy  metals  in  being  essential  to  the 
life  of  many,  perhaps  all,  forms  of  protoplasm.  In  the  vertebrates  this 
is  obscured  by  the  fact  that  most  of  the  iron  is  contained  in  the  haemo- 
globin of  the  blood,  and  its  importance  in  the  other  tissues  is  generally 
ignored.  In  the  invertebrates,  however,  in  many  of  which  no  corre- 
sponding compound  exists  in  the  blood,  considerable  amounts  of  iron 
are  found  in  the  tissues,  and  there  is  no  question  that  throughout  the 
animal  kingdom  iron  is  essential  to  living  matter,  quite  apart  from  its 
special  relation  to  the  blood  in  the  vertebrates.  Molisch  has  shown 
that  it  is  also  necessary  for  the  development  of  the  lower  vegetable 
forms,  and  it  has  been  found  that  in  its  absence  the  higher  plants  fail 
to  form  chlorophyll,  although  iron  is  not  actually  contained  in  the 
latter  as  it  is  in  haemoglobin. 

The  iron  combinations  are  generally  divided  into  two  classes — in- 
organic and  organic.1  In  the  former  of  these  iron  is  contained  in  the 
ordinary  salt  form,  is  dissociated  in  solution,  and  can  be  recognized  by 
such  tests  as  the  black  precipitate  with  ammonium  sulphide,  and  the 
blue  precipitates  with  the  ferrocyanide  or  ferricyanide  of  potassium.  In 
organic  iron  these  tests  fail,  or  are  only  elicited  after  prolonged  contact, 
as  the  iron  ion  is  less  readily  dissociated.  Examples  of  inorganic 
iron  are  the  chlorides,  acetates  or  sulphates,  while  the  best  type  of 
organic  iron  is  haemoglobin,  though  numbers  of  others  exist  in  the 
tissues.  Between  the  ordinary  salts  of  iron  and  haemoglobin  and  its 
allies  there  exists  a  number  of  compounds  which  are  stained  black  by 
ammonium  sulphide  after  prolonged  contact,  and  which  it  is  impossible 
to  class  either  as  organic  or  inorganic. 

111  Organic"  and  "inorganic"  are  here  used  in  a  special  meaning,  and  have  no 
reference  to  the  combination  to  which  iron  is  attached,  but  to  the  method  of  attach- 
ment. Thus  the  acetate  and  albuminate  of  iron  are  both  classified  among  the  inorganic 
iron  compounds,  because  they  are  capable  of  dissociation,  and  the  iron  is  precipitated 
by  ammonium  sulphide.  " Masked  iron"  is  a  preferable  term  for  "organic  iron," 
but  has  not  been  so  widely  used. 


656  THE  HEA  VY  METALS. 

When  such  a  salt  as  the  perchloride  is  added  to  a  solution  of  proteid, 
it  precipitates  it  at  once  in  the  form  of  iron  albuminate.  This  insolu- 
ble body  is  also  formed  in  the  living  tissues  when  the  perchloride  is 
brought  in  contact  with  them,  and  forms  a  protective  coating  on  the 
surface.  Iron  has  no  such  relation  to  the  proteids  as  mercury,  and 
does  not  corrode  them  of  itself,  any  destruction  which  may  be  caused 
by  such  compounds  as  the  perchloride  being  due  to  the  acid  constituent 
and  not  to  the  metallic  ion.  The  albuminate  is  not  so  flocculent  as 
that  of  mercury,  and  tends  to  protect  the  tissues  from  the  acid,  so  that 
the  corrosion  of  iron  compounds  is  limited  to  the  surface.  The  double 
salts  of  iron,  the  albuminous  compounds,  and  organic  iron  do  not  pre- 
cipitate proteids,  and  are  therefore  neither  irritant  nor  astringent  aa 
long  as  they  maintain  their  original  form  and  are  not  decomposed  into 
simple  salts. 

Symptoms. — Inorganic  iron  compounds,  of  which  the  perchloride 
may  be  taken  as  a  type,  have  an  astringent,  metallic,  or  often  acid 
taste,  but  in  ordinary  doses  induce  no  further  symptoms.  If  swal- 
lowed in  large  quantities,  they  cause  pain  and  uneasiness  in  the  stom- 
ach, nausea,  vomiting  and  often  purging,  with  all  the  ordinary  symp- 
toms of  acute  gastro-intestinal  irritation.  General  weakness  and  even 
collapse  may  be  induced,  but  are  manifestly  secondary  to  the  gastric 
and  intestinal  effects,  and  no  symptoms  which  can  in  any  way  be  at- 
tributed to  the  absorption  of  iron  have  been  observed  in  either  man 
or  animals. 

The  prolonged  use  of  inorganic  iron  is  frequently  followed  by  some 
dyspepsia,  and  by  constipation  and  colic,  which  are  obviously  due  to 
the  continued  astringent  action  on  the  stomach  and  bowel.  Other 
symptoms  observed  occasionally  are  blackness  of  the  teeth  and  tender- 
ness in  the  gums,  which  may  be  due  to  the  acid  contained  in  many 
iron  preparations  ;  the  blackening  of  the  teeth  has  been  supposed  to  be 
due  to  the  tannic  acid  of  the  food  precipitating  the  inky  black  tannate 
of  iron,  or  to  the  sulphide  of  iron  being  formed  by  the  action  of  the 
hydrogen  sulphide  present  in  carious  teeth.  According  to  Buzdygan, 
the  iron  preparations  increase  the  secretion  of  hydrochloric  acid  in  the 
stomach,  and  may  thus  lead  to  hyperacidity,  or  aggravate  it  if  already 
present.  In  artificial  digestion,  the  salts  of  iron  with  organic  acids 
are  said  to  hinder  the  process  more  than  those  with  inorganic  acids, 
the  ferric  salts  more  than  the  ferrous,  and  the  insoluble  preparations 
least  of  all.  The  digestion  of  starch  is  almost  unaffected  by  the  pres- 
ence of  iron. 

Iron  given  by  the  mouth  induces  leucocytosis  (Pohl),  and  does  not 
affect  the  amount  of  double  sulphates  excreted  in  the  urine,  so  that  it 
has  no  antiseptic  action  in  the  bowel  (Morner). 

Some  symptoms  from  the  circulation  are  sometimes  said  to  arise,  but  are 
for  the  most  part  subjective,  and  seem  to  be  handed  down  by  tradition  rather 
than  really  observed.  These  are  a  feeling  of  congestion,  fulness  and  heat  in 
the  head,  and  haemorrhages  from  the  nose,  throat  and  lungs,  especially  in 
phthisis.  If  these  symptoms  are  not  entirely  imaginary,  they  are  to  be 


IRON.  657 

attributed  to  some  reflex  from   the   stomach   and    intestine   and   not  to   any 
direct  action  of  iron  on  the  heart  or  vessels. 

When  these  astringent  preparations  are  injected  into  the  blood  vessels  in 
animals,  they  coagulate  the  proteids  and  cause  thrombosis  but  no  real 
symptoms  of  iron  poisoning.  Fatal  thrombosis  has  been  observed  in  patients 
from  the  injection  of  the  perchloride  into  the  uterus,  and  also  into  nsevi. 
The  hypodermic  injection  of  these  salts  causes  some  pain  and  swelling,  but 
no  further  symptoms  follow,  and  the  iron  is  found  for  the  most  part  deposited 
in  an  insoluble  form  at  the  point  of  injection. 

The  General  Symptoms  of  iron  are  obtained  only  by  the  intravenous  in- 
jection of  double  salts,  such  as  the  tartrate  of  iron  and  sodium,  which  do  not 
coagulate  the  blood,  and  at  the  same  time  are  capable  of  freeing  the  iron 
ion  in  the  tissues.  Such  salts  as  the  ferrocyanides  or  ferricyanides  on  the 
other  hand  leave  the  body  as  such,  and  the  iron  ion  is  not  liberated,  so  that 
no  iron  symptoms  are  induced.  Meyer  and  Williams  found  that  the  double 
tartrate  caused  in  the  frog  slowness  and  clumsiness  in  movement,  which 
gradually  developed  into  complete  paralysis  of  the  central  nervous  system. 
The  heart  seemed  to  be  little  affected,  but  the  skeletal  muscles  were  some- 
what less  irritable  than  usual  after  death.  In  mammals,  the  symptoms  of 
iron  poisoning  were  often  very  late  in  appearing,  and  began  with  some 
acceleration  of  the  breathing,  which  later  became  slow  and  dyspnoeic ; 
vomiting  and  diarrhoea  often  followed,  and  blood  was  sometimes  seen  in  the 
evacuations  of  the  stomach  and  bowel.  Increasing  weakness  was  followed 
by  central  paralysis  and  death,  accompanied  by  weak  convulsive  movements. 
The  heart  seemed  little  affected,  although  the  blood-pressure  fell  rapidly 
towards  the  end.  Post-mortem,  the  mucous  membranes  of  the  stomach  and 
intestine  were  found  swollen  and  congested,  and  often  contained  numerous 
small  blood  extravasations.  Kobert  found  that  repeated  injection  of  small 
quantities  of  the  citrate  of  iron  induces  congestion  of  the  kidney  and  the  ap- 
pearance of  casts  and  albumin  in  the  urine.  In  acute  poisoning  the  alka- 
linity of  the  blood  is  reduced  owing  to  the  excess  of  lactic  acid  formed. 

Iron,  like  the  other  heavy  metals,  would  therefore  seem  to  have  a  specific 
irritant  effect  on  the  intestinal  and  gastric  mucous  membrane,  and  to  a  less 
extent  on  the  kidney.  In  addition,  it  depresses  and  eventually  paralyzes 
the  central  nervous  system,  but  it  is  impossible  to  state  how  far  this  is  due 
to  direct  action,  and  how  far  it  is  secondary  to  the  action  in  the  alimentary 
canal. 

According  to  Kobert,  iron  perfused  through  the  vessels  has  no  effect  on 
their  calibre  except  in  large  doses,  when  it  dilates  them.  The  astringent 
action  is  due,  therefore,  to  the  precipitation  of  the  proteids,  and  not  to  con- 
striction of  the  vessels. 

Apart  from  irritation  of  the  stomach  and  intestine,  no  symptoms  are 
induced  by  iron  given  by  the  mouth,  because  it  is  absorbed  too  slowly  and 
in  too  small  amount,  and  perhaps  in  a  form  which  has  little  tendency  to 
cause  them. 

The  Absorption  of  Iron  has  been  a  subject  of  discussion  only  during 
the  latter  half  of  the  last  century,  for  up  to  that  time  it  had  been  assumed 
that  it  passed  into  the  tissues  with  comparative  ease,  and  was  there 
formed  to  haemoglobin.  In  this  way  was  explained  its  effect  in 
anaemia,  particularly  in  the  form  known  as  chlorosis,  in  which  there  is 
a  deficiency  of  haemoglobin  rather  than  of  blood  cells.  The  benefit 
accruing  from  the  use  of  iron  salts  in  this  disease  has  been  attested  by 
so  many  generations  of  physicians  that  only  the  most  skeptical  can 
have  any  doubt  on  the  subject.  The  first  to  question  this  explanation 
of  the  action  of  iron  in  chlorosis  was  Kletzinsky,  who  formulated  a 
42 


658  THE  HEAVY  METALS. 

theory  of  its  action,  which  was  soon  forgotten,  however,  and  only 
became  popularly  known  when  it  was  resuscitated  by  Bunge.  This 
explanation,  which  is  generally  stated  as  Bunge's  theory,  has  been 
widely  held  during  the  last  few  years,  but  has  now  been  abandoned  by 
almost  all  its  former  supporters  including  its  author,  who  has  been 
compelled  to  admit  not  only  that  iron  salts  are  absorbed  but  that  their 
administration  leads  to  an  increased  formation  of  haemoglobin. 

No  account  of  the  action  of  iron  would  be  complete,  however,  without 
reference  to  an  explanation,  which  has  at  least  had  the  effect  of  establishing 
a  number  of  facts  regarding  the  fate  of  iron  in  the  body,  and  also  the  less 
desirable  result  of  increasing  to  a  considerable  extent  the  number  of  pat- 
ented preparations  containing  iron.  Shortly  stated,  Bunge's  theory  is  that 
in  ordinary  conditions  a  certain  amount  of  iron  is  lost  by  the  body  constantly 
through  the  excretions,  and  this  loss  is  made  up  by  the  absorption  of  the  iron 
contained  in  the  food.  This  food-iron  consists  wholly  of  organic  iron,  that 
is,  of  iron  combined  in  such  a  way  that  sulphides  attack  it  with  difficulty  ; 
an  example  of  such  organic  iron  is  the  haematogen  of  the  yolk  of  egg.  In 
normal  individuals  the  food-iron  is  sufficient  to  replace  that  lost  by  excre- 
tion, but  in  chlorosis  the  presence  of  large  amounts  of  sulphides  in  the  in- 
testine causes  the  food-irons  to  be  decomposed  to  ferric  sulphide,  which  is 
insoluble  and  unabsorbable.  When  the  ordinary  inorganic  iron  prepara- 
tions are  administered  in  these  cases,  they  are  not  taken  up  in  place  of 
the  food-irons ;  but,  by  forming  sulphide  in  the  intestine,  they  remove  the 
sulphuretted  hydrogen,  and  prevent  the  decomposition  of  the  food-irons, 
which  thus  remain  capable  of  being  absorbed.  Bunge  and  his  followers 
went  on  to  state  that  inorganic  iron  is  never  under  any  circumstances  ab- 
sorbed by  the  normal  epithelium,  but  that  when  large  quantities  are  admin- 
istered, they  tend  to  corrode  the  walls  of  the  stomach  and  intestine,  and  are 
thus  absorbed  to  some  extent.  Even  then,  however,  they  are  incapable  of 
being  formed  to  haemoglobin,  the  animal  body  being  able  to  perform  only 
the  last  steps  of  this  synthesis,  after  the  plants  have  formed  the  simpler 
types  of  organic  iron.  This  theory  now  possesses  only  historical  interest,  so 
that  it  is  unnecessary  to  enumerate  the  arguments  brought  against  it.  It 
may  be  sufficient  to  state  that  if  the  ordinary  preparations  of  iron  acted  only 
by  binding  the  sulphides  of  the  intestine,  various  other  metals  would  be 
equally  efficient  in  chlorosis  ;  iron  would  not  be  beneficial  injected  hypoder- 
mically,  and  iron  sulphide  given  so  as  to  escape  the  action  of  the  gastric 
juice  would  be  equally  useless.  It  is  found,  however,  that  no  other  metal 
can  replace  iron  in  chlorosis  ;  that  iron  injected  hypodermically  is  curative 
in  chlorosis,  and  that  the  sulphide  administered  so  as  to  reach  the  intestine 
unchanged,  acts  as  well  as  other  preparations  (Stockman).  Finally,  it  has 
been  shown  that  ordinary  preparations  of  iron  are  absorbed. 

Driven  from  their  former  position  that  inorganic  iron  is  not  absorbed  by 
the  intestine,  the  advocates  of  the  use  of  organic  iron  in  chlorosis  have  at- 
tempted to  make  a  further  stand  by  asserting  that,  although  the  ordinary 
preparations  are  absorbed,  they  are  not  used  in  the  formation  of  haemoglobin, 
but  after  a  more  or  less  prolonged  stay  in  the  liver  and  other  organs,  are 
excreted.  This  statement  is  refuted,  however,  by  several  researches,  in 
which  the  addition  of  inorganic  iron  to  food  deficient  in  iron  (milk),  or 
entirely  free  from  it,  prevented  the  anaemia  which  was  observed  in  animals 
fed  on  the  same  food,  but  without  iron.  Finally  Abderhalden,  the  latest  ex- 
ponent of  Bunge's  views,  finds  that  inorganic  iron  increases  the  haemoglobin 
of  the  blood,  but  suggests  that  it  may  do  so  indirectly  by  taking  the  place  of 
the  food-iron  which  supplies  the  needs  of  the  tissues,  the  food-iron  then  being 
formed  to  haemoglobin  ;  he  fails  to  supply  any  arguments  in  support  of  this 
theory,  which  it  is  therefore  unnecessary  to  discuss. 


IEON.  659 

The  chief  difficulties  in  following  the  course  of  iron  in  the  body  are 
due  to  its  being  present  in  all  the  tissues  and  secretions  normally,  and 
to  the  very  small  quantity  which  is  contained  in  ordinary  food,  and 
which  is  essential  to  the  maintenance  of  health.  About  2J-3J  G. 
(40-55  grs.)  of  iron  are  estimated  to  be  present  in  the  tissues  of  a 
healthy  human  adult,  the  greater  part  of  it  existing  in  the  form  of 
haemoglobin  in  the  blood.  Formerly  it  was  believed  that  some  50 
mgs.  (1  gr.)  of  iron  were  taken  in  the  food  per  day,  but  Stockman  and 
Greig  have  recently  shown  that  this  estimate  is  much  too  high,  and 
that  an  ordinary  dietary  provides  only  about  5-10  mgs.  (-j1^— J  gr.)  of 
iron  per  day ;  they  found  in  one  case  that  even  3-5  mgs.  (^V~lV  &r") 
were  sufficient  to  preserve  the  iron  equilibrium.  About  the  same 
amount  of  iron  is  excreted  per  day,  chiefly  in  the  faeces,  to  a  much 
smaller  extent  in  the  urine. 

When  additional  iron  is  supplied  to  the  body,  either  as  inorganic  or 
as  organic  iron,  much  the  greater  part  of  it  reappears  in  the  stools. 
This  does  not  necessarily  entail  that  all  of  it  has  passed  through  the 
bowel  unabsorbed,  for  it  is  now  perfectly  certain  that  iron  is  excreted 
through  the  intestinal  epithelium,  so  that  some  of  the  iron  of  the  stools 
may  have  been  absorbed  and  reexcreted.  The  strongest  argument  cited 
by  Bunge  in  support  of  his  theory  was  that  inorganic  iron,  given  by 
the  mouth,  did  not  increase  the  iron  of  the  urine.  He  assumed  that 
any  iron  absorbed  would  necessarily  appear  in  course  of  time  in  the 
urine,  but  this  has  been  shown  to  be  incorrect  by  a  whole  series  of  in- 
vestigations. When  iron  salts  such  as  the  double  tartrate  are  injected 
into  a  vein,  they  soon  disappear  from  the  blood,  but  only  some  2-5 
per  cent,  of  the  quantity  injected  reappears  in  the  urine,  the  rest  being 
withdrawn  from  the  blood  and  stored  up  in  the  cells  of  the  liver  and 
spleen,  and  perhaps  in  the  bone-marrow.  Thus  even  if  iron  is  ab- 
sorbed in  the  intestine,  it  is  improbable  that  it  will  reappear  in  the 
urine  in  appreciable  quantity,  for  supposing  10  mgs.  to  be  taken  up,  2 
per  cent,  of  this  would  represent  only  ^  mg.  and  this  lies  within  the 
limits  of  error  of  estimation.  In  addition,  it  seems  probable  that  when 
iron  enters  the  blood  slowly  and  in  small  quantities,  even  a  less  pro- 
portion of  it  is  excreted  in  the  urine  than  when  larger  quantities  are 
injected  suddenly.  On  the  whole  the  evidence  goes  to  show  that 
0.5-1.5  mgs.  of  iron  are  normally  excreted  in  the  urine  in  24  hours, 
and  that  the  administration  per  os  of  iron  preparations,  whether  organic 
or  inorganic,  does  not  affect  this  amount.  The  fact  that  an  iron 
preparation  given  by  the  mouth  does  not  increase  the  iron  in  the  urine 
is  therefore  no  evidence  that  it  has  not  been  absorbed  from  the  stomach. 

Iron  injected  into  the  veins  of  normal  animals  is  stored  up  in  the 
liver  and  spleen,  but  is  slowly  taken  up  from  these  organs  again,  and 
is  excreted  by  the  epithelium  of  the  caecum  and  colon.  When  iron  is 
given  by  the  mouth,  therefore,  it  may  either  pass  along  the  canal  and 
be  thrown  out  in  the  faeces,  or  it  may  be  absorbed,  make  a  stay  in  the 
liver,  be  excreted  in  the  large  intestine,  and  again  appear  in  the  stools. 
The  comparison  of  the  iron  in  the  food  and  in  drugs  with  that  of  the 


660  THE  HEAVY  METALS. 

stools  therefore  gives  no  clue  as  to  how  much  has  been  absorbed,  and 
how  much  has  simply  passed  through  the  intestine. 

But  the  passage  of  iron  from  the  liver  to  the  intestine  is  a  somewhat 
slow  process,  and  it  is  therefore  possible  to  detect  the  excess  of  iron  in 
the  liver.  This  has  been  done  repeatedly  by  the  following  method. 
Young  animals  of  the  same  litter  fed  on  milk  have  approximately  the 
same  amount  of  iron  in  the  liver.  If  one  be  fed  on  milk  only,  the 
other  on  milk  to  which  iron  is  added,  the  .liver  of  the  latter  is  found 
to  contain  more  iron  than  that  of  the  control.  Other  investigators 
have  fed  animals  (rats  or  mice)  on  food  that  is  practically  free  from 
iron,  have  killed  them  and  estimated  the  iron  in  the  whole  body  apart 
from  the  alimentary  tract  and  compared  it  with  that  of  animals  treated 
in  the  same  way  except  that  iron  was  added  to  the  food.  The  latter 
group  contains  much  more  iron  than  the  control  group  fed  on  iron-free 
food,  and  in  general  presents  a  much  more  healthy  and  normal  ap- 
pearance. 

Finally,  attempts  have  been  made  to  follow  the  iron  in  its  course 
through  the  tissues.  This  is  possible  by  the  histological  examination 
of  tissues  soaked  in  ammonium  sulphide  solution,  in  potassic  ferrocy- 
anide  and  hydrochloric  acid,  or  in  haBmatoxylin,  as  these  form  black 
or  blue  precipitates  with  most  forms  of  iron,  but  leave  the  haemoglobin 
unaffected.  When  animals  are  given  iron  preparations,  and  are  'then 
killed,  and  their  organs  stained  by  these  reagents,  the  mucous  mem- 
brane of  the  stomach  and  of  the  greater  part  of  the  small  intestine  gives 
no  coloration,  but  the  epithelium  of  the  duodenum  and  the  upper  part 
of  the  jejunum  is  found  to  contain  numerous  granules  of  iron.  These 
granules  may  be  traced  to  the  mesenteric  lymph  glands,  are  found  in 
large  numbers  in  the  spleen  around  the  corpuscles,  to  a  much  smaller 
extent  in  the  liver,  and  in  the  cortex  of  the  kidney.  If,  however,  the 
animal  be  kept  for  some  days  after  the  iron  is  given,  the  reaction  in 
the  duodenum,  spleen,  and  mesenteric  glands  is  less  intense,  while  the 
liver  gives  much  more  distinct  evidence  of  containing  iron,  and  the 
epithelial  cells  of  the  large  intestine  and  caecum  also  give  a  strong 
reaction.  This  is  interpreted  to  mean  that  iron  is  absorbed  by  the 
duodenum  and  is  first  stored  in  the  spleen,  but  later  finds  its  way 
through  the  blood  vessels  to  the  liver,  where  it  rests  again  for  some 
time,  to  be  eventually  taken  up  again  by  the  blood  and  excreted  into 
the  large  intestine  and  the  caecum.  There  is  some  question  as  to 
whether  the  lymph  vessels  are  involved  in  the  absorption  of  iron  and 
the  most  recent  investigators  have  failed  to  find  it  in  the  thoracic  duct 
and  accordingly  hold  that  it  is  absorbed  from  the  intestine  into  the 
blood  vessels  directly.  The  iron  stored  in  the  liver  does  not  escape 
by  the  bile  as  might  be  anticipated.  A  small  percentage  of  iron  is  a 
constant  constituent  of  this  fluid,  but  is  not  increased  by  iron  given  by 
the  mouth  or  intravenously. 

Nothing  is  known  with  certainty  regarding  the  form  in  which  iron 
is  absorbed.  It  is  assumed  that  in  the  stomach  almost  all  the  prepa- 


IRON.  661 

rations  form  chlorides  to  a  greater  or  less  extent,1  are  then  changed 
into  albuminates,  and  in  this  form  pass  into  the  duodenum,  where  they 
may  be  absorbed  in  solution,  or  may  be  precipitated  and  taken  up  as 
solids  by  the  epithelial  cells  and  the  leucocytes.  In  the  liver  it  seems 
likely  that  the  absorbed  iron  is  changed  to  hepatic  ferratin,  and  that  it 
is  stored  in  this  form.  Several  other  iron  compounds  have  been  found 
in  the  liver,  and  iron  undoubtedly  undergoes  a  number  of  synthetic 
processes  there. 

It  must  not  be  inferred  from  the  foregoing  that  all  of  the  inorganic 
iron  swallowed  is  taken  up  by  the  intestinal  epithelium.  It  is  quite 
impossible  to  form  even  approximate  estimates  of  the  amount  that  is 
really  absorbed  and  made  use  of  by  the  tissues,  but  the  probability 
is  that  only  a  small  percentage  is  really  taken  up ;  the  rest  passing 
through  the  intestine  and  being  thrown  out  in  the  stools.  It  is  often 
stated  that  the  iron  stools  are  dark  or  black  in  color,  from  the  sulphide 
present,  but  this  seems  to  be  seldom  the  case  when  they  are  passed, 
although  they  assume  a  darker  gray  or  grayish  black  color  in  the  air 
from  oxidation.  The  iron  is  contained  in  them  only  to  a  small  extent 
as  the  sulphide,  some  of  the  rest  probably  being  albuminate. 

To  sum  up  what  is  known  regarding  the  fate  of  the  iron  preparations, 
they  are  partially  formed  to  the  chloride  and  then  to  the  albuminate  in 
the  stomach,  pass  into  the  duodenum,  from  which  the  great  bulk  is  car- 
ried on  into  the  lower  parts  of  the  intestine,  while  some  is  absorbed  by 
the  epithelium  and  leucocytes  in  solid  form  and  perhaps  in  solution. 
It  is  then  deposited  in  the  spleen,  where  it  may  undergo  some  changes 
in  form,  is  later  taken  up  by  the  blood  and  deposited  in  the  liver  and 
perhaps  in  the  bone  marrow.  Where  the  supply  of  iron  has  been 
inadequate  for  the  formation  of  haemoglobin,  the  originally  inorganic 
iron  is  probably  worked  into  higher  forms  and  eventually  into  haemo- 
globin in  the  liver,  and  it  seems  likely  that  ferratin  is  one  of  the 
intermediate  steps  in  this  synthesis.  When  there  is  no  deficiency  of 
iron  for  the  formation  of  haemoglobin,  the  liver  slowly  yields  its  store 
of  iron  to  the  blood,  which  carries  it  to  the  caecum  and  large  intestine, 
by  the  epithelium  of  which  it  is  finally  excreted.  It  is  to  be  noted 
that  the  iron  absorbed  does  not  increase  the  amount  of  iron  in  the 
urine,  bile  or  other  excretions.  The  investigations  on  which  this  sketch 
is  founded  have  been  completed  only  in  the  last  few  years,  and  establish 
finally  the  truth  of  the  position  held  by  the  older  physicians  and  indeed 
by  the  clinicians  of  this  later  time  also,  that  inorganic  iron  follows  the 
same  course  in  the  tissues  as  food- iron,  although  possibly  more  of  the 
latter  is  absorbed. 

But  this  explanation  of  the  iron  action  does  not  cover  all  the  diffi- 
culties of  the  case.  Many  cases  of  chlorosis  recover  without  inorganic 
iron  under  hygienic  conditions,  such  as  rest,  and  particularly  when 
foods  rich  in  iron  are  prescribed,  this  being  exactly  what  is  to  be  ex- 
pected on  the  theory  that  inorganic  iron  merely  takes  the  place  of  the 

1  According  to  several  of  the  older  authors  the  ferric  salts  are  changed  to  ferrous  in 
the  stomach. 


662  THE  HEAVY  METALS. 

deficient  food-iron.  But  many  chlorotic  patients  show  little  or  no 
improvement  when  treated  with  foods  containing  iron,  even  when  there 
is  no  question  that  the  iron  supplied  daily  in  food  form  is  sufficient  for 
the  needs  of  the  economy,  and  chlorosis  even  appears  in  individuals 
who  have  never  suffered  from  any  deficiency  of  food-iron.  Yet  many 
of  these  cases  recover  rapidly  under  inorganic  iron.  V.  Noorden  has 
attempted  to  explain  this  by  supposing  that  inorganic  iron  when 
absorbed  acts  as  a  stimulant  to  the  blood-forming  organs,  while  food-- 
iron has  no  such  property.  And  some  indications  of  abnormal  activity 
of  the  bone-marrow  cells  have  been  observed  in  animals  supplied  with 
inorganic  iron ;  this  may  not  be  the  effect  of  stimulation  in  the  ordi- 
nary sense  of  the  word,  however,  for  it  may  be  explained  by  the  un- 
usual abundance  of  the  materials  necessary  to  their  activity.  The 
difference  in  the  effects  of  the  irons  of  the  food  and  of  the  inorganic 
preparations  may  be  due  to  the  fact  that  food-iron  is  always  accom- 
panied by  a  large  amount  of  colloid  material,  which  may  materially 
delay  its  absorption  while  inorganic  iron  on  the  other  hand  is  much 
less  completely  enveloped,  and  may  be  more  easily  absorbed.  In  ad- 
dition, the  iron  preparations  are  given  in  much  larger  amounts  than 
the  food-irons.  When  10  mgs.  (food-iron)  are  taken  per  day,  only  a 
small  proportion  (e.  g.,  5  mgs.)  may  be  absorbed,  and  this  may  be 
insufficient  to  supply  the  needs  of  the  body,  but  if  some  hundreds  of 
milligrams  of  inorganic  iron  be  added,  the  proportion  absorbed  will  be 
amply  sufficient.  The  same  effect  might  be  obtained  by  the  same 
amount  of  food-iron,  but  this  is  only  to  be  obtained  by  giving  more 
food  than  can  be  digested. 

Iron  is  not  absorbed  from  the  unbroken  skin,  and  the  iron  and  steel 
baths  are  therefore  of  no  value  in  themselves  in  the  treatment  of 
anaemia. 

Therapeutic  Uses.  —  Iron  is  most  frequently  used  in  the  treatment  of 
Chlorosis,  which  in  a  large  proportion  of  cases  recovers  entirely  under 
it.  Some  cases,  however,  improve  somewhat  under  iron,  but  relapse 
when  it  is  left  off,  and  a  certain  number  of  patients  show  no  improve- 
ment whatever  under  it.  These  last  are  not  generally  regarded  as 
suffering  from  chlorosis  proper,  but  from  a  more  malignant  form  of 
anaemia.  A  number  of  symptoms  which  are  due  to  chlorosis,  and 
which  are  often  more  prominent  than  the  original  disease,  are  also  re- 
lieved or  entirely  removed  by  iron.  Thus  gastric  catarrh,  amenorrhoaa, 
or  oedema  may  disappear  under  it,  but  in  these  cases  the  symptoms 
are  chlorotic  in  origin,  and  the  improvement  is  due  to  the  increased 
haemoglobin,  and  not  to  the  direct  action  of  iron  on  the  stomach,  uterus 
or  circulation.  In  chlorosis,  the  iron  is  generally  given  in  small  doses, 
at  any  rate  at  first,  and  the  less  astringent  preparations  are  preferred 
by  most  clinicians,  although  some  still  advise  the  perchloride.  When 
chlorosis  is  complicated  with  gastric  catarrh,  some  authorities  advise 
that  the  latter  be  treated  before  the  general  condition,  as  iron  in  itself 
is  liable  to  irritate  the  stomach.  In  many  cases,  however,  the  catarrh 
is  secondary  to  the  chlorosis,  and  can  only  be  treated  successfully  by 


IRON.  663 

improving  the  condition  of  the  blood ;  the  iron  preparation  here  ought 
to  be  mild  and  not  irritating.  In  chlorosis  the  tendency  to  constipa- 
tion may  be  increased  by  iron,  and  a  purge  is  often  required,  such  as 
the  iron  and  aloes  pill,  which  is  particularly  recommended  when  chlo- 
rosis is  attended  by  amenorrhoaa. 

Iron  is  of  less  value  in  other  forms  of  anaemia,  although  it  is  often 
prescribed  and  may  be  followed  by  some  improvement.  Thus  it  may 
be  administered  during  convalescence  from  acute  disease,  such  as 
typhoid  fever,  or  nephritis,  and  in  the  anaemia  induced  by  profuse 
haemorrhage,  iron  often  seems  to  accelerate  the  recuperation  of  the 
blood.  It  is  often  prescribed  for  the  cachexia  of  malaria,  syphilis  and 
other  chronic  diseases. 

Iron  is  said  to  be  contraindicated  where  there  is  fever,  in  plethoric 
individuals  with  a  tendency  to  haemorrhages,  and  in  some  forms  of 
heart  disease.  In  these  conditions  the  iron  preparations  can  harm 
only  from  a  reflex  induced  from  the  stomach,  as  the  small  quantity  of 
iron  absorbed  is  incapable  of  producing  any  effects  in  the  tissues.  In 
phthisis,  it  is  very  generally  credited  with  causing  haemorrhage  from 
the  lungs,  but  it  may  be  questioned  how  far  this  apprehension  is  based 
on  observation,  and  how  far  it  is  a  relic  of  old  and  forgotten  theories 
of  the  action  of  iron.  It  has  to  be  given  with  caution  here  in  order 
to  avoid  irritation  of  the  stomach  and  dyspepsia,  and  in  the  presence 
of  gastric  catarrh  from  any  cause,  its  effects  have  to  be  watched  care- 
fully. 

Some  of  the  older  authorities  advise  iron  to  be  given  in  large  quan- 
tities, but  the  dose  has  been  reduced  of  late  years  to  about  0.1-0.2 
G.  (2-3  grs.)  three  times  a  day.  It  is  given  after  meals  in  order  to 
avoid  the  irritant  action  on  the  stomach  as  far  as  possible.  It  is  to  be 
noted  that  on  giving  0.1  G.  of  iron  three  times  a  day,  about  thirty 
times  as  much  iron  is  given  as  is  required  normally  in  food,  so  that 
the  chlorotic  receives  more  iron  per  day  than  a  workman  in  a  month. 

Iron  is  occasionally  injected  hypoderinically,  with  the  object  of 
avoiding  the  irritation  of  the  stomach,  but  this  procedure  is  painful 
and  causes  some  swelling  and  irritation,  which  lasts  twenty-four  hours 
or  more.  Most  of  the  salts  are  precipitated  at  the  point  of  injection, 
but  some,  such  as  the  citrate,  are  taken  up  by  the  blood  at  once ;  the 
danger  of  renal  irritation,  anticipated  by  Kobert,  does  not  seem  to. 
arise  if  small  quantities  are  used.  The  citrate  and  pyro-phosphate  in 
5  per  cent,  solution  have  been  used  in  this  way,  0.05-0.1  G.  (1-2  grs.) 
of  the  salt  being  injected  daily.  The  hydrate  and  oxide  have  also 
been  injected,  suspended  in  salt  solution,  but  are  somewhat  more  irri- 
tant, while  the  peptonate  is  recommended  as  being  almost  devoid  of 
irritant  qualities. 

Iron  has  been  recommended  in  erysipelas,  but  has  proved  valueless 
in  the  hands  of  most  investigators.  Some  of  the  iron  salts  are  employed 
as  Astringents,  the  most  popular  preparations  for  this  purpose  being  the 
ferrous  sulphate,  which  has  been  used  to  some  extent  in  diarrhoaa,  and 
also  externally.  The  perchloride  is  perhaps  the  best  Styptic  of  its 


664  THE  HEAVY  METALS. 

class.  When  applied  to  a  bleeding  point,  it  precipitates  the  proteids  of 
the  blood  plasma,  and  thus  forms  an  obstruction  to  the  flow  of  blood 
similar  to  that  caused  by  clotting,  although  no  fibrin,  but  only  a  mass 
of  iron  albuminate,  is  formed  by  the  perchloride.  This  styptic  action 
is  of  value  in  capillary  and  recurrent  haemorrhage,  while  in  bleed- 
ing from  an  artery,  the  ordinary  surgical  methods  are  of  course  pre- 
ferred. The  chloride  arrests  hemorrhage  only  when  it  can  be  brought 
into  actual  contact  with  the  bleeding  point,  and  where  this  is  covered 
by  a  large  mass  of  semicoagulated  blood,  the  treatment  is  of  no  avail, 
as  it  simply  forms  the  albuminate  with  the  blood  with  .which  it  comes 
into  contact  first,  and  this  may  be  far  from  the  actual  point  of  rupture. 
As  an  application  to  the  stomach  and  bowel  in  hemorrhage  from  these 
parts,  the  perchloride  is  unlikely  to  prove  successful,  while  in  bleed- 
ing from  the  nose,  or  gums,  or  after  the  extraction  of  a  tooth,  it  is 
more  reliable.  It  has  been  injected  into  the  uterus  in  haemorrhage, 
into  nevus  in  order  to  cause  coagulation  and  subsequent  cicatrization 
of  the  tissue,  and  into  aneurisms.  This  is  a  very  dangerous  treat- 
ment, however,  for  several  cases  of  fatal  embolism  have  arisen  from 
the  precipitated  albuminate  being  carried  off  in  the  veins.  Perchloride 
of  iron  solution  has  been  sprayed  into  the  air  passages  in  hemoptysis, 
but  if  sufficiently  concentrated  to  coagulate  the  blood  at  the  bleeding 
point  in  the  lungs,  it  would  certainly  induce  irritation  and  coughing. 
The  perchloride  is,  of  course,  valueless  in  hemorrhage  from  internal 
organs,  for  in  the  first  place,  very  little  of  it  is  absorbed,  and  in  the 
second  place,  what  does  pass  into  the  tissues  is  already  in  proteid  com- 
bination, and  therefore  incapable  of  coagulating  the  blood.  The  same 
objection  applies  to  the  alleged  astringent  effect  of  iron  in  nephritis. 
It  is  possible  that  iron  may  lessen  the  albumin  in  the  urine  in  these 
cases,  although  the  clinical  evidence  is  contradictory  on  the  subject, 
but  it  is  absolutely  certain  that  it  does  not  do  so  by  any  local  action 
on  the  albumin  in  the  kidney. 

The  sulphate  of  iron  is  used  as  a  disinfectant  for  sewage.  It  acts 
here  merely  by  precipitating  the  proteids,  which  carry  down  the  bac- 
teria mechanically.  The  proteids  of  the  sewage  may  be  increased  by 
the  addition  of  blood  before  the  sulphate  is  applied.  The  sulphate  of 
iron  is  used,  because  it  is  cheaper  than  the  other  salts  of  the  heavy 
metals. 

PREPARATIONS. 

Ferri  Chloridum  (U.  S.  P.),  ferric  chloride  (Fe2Cl6-fl2H2O),  orange  yellow 
crystals,  with  a  strong  astringent  taste,  very  deliquescent  in  air,  soluble  in 
water  and  alcohol. 

Liquor  Ferri  Chloridi  (U.  S.  P.),  a  solution  of  ferric  chloride  containing 
about  37.8  per  cent,  of  the  anhydrous  salt  or  about  13  per  cent,  of  iron. 

TINCTURA  FERRI  CHLORIDI  (U.  S.  P.)  is  formed  from  the  liquor  by  dilut- 
ing it  with  3  parts  of  alcohol.  0.5-2  c.c.  (8-30  mins.). 

Liquor  Ferri  Perchloridi  Fortis  (B.  P.)  is  formed  by  dissolving  iron  in  hy- 
drochloric acid,  and  contains  22 £  per  cent,  of  iron.  It  is  an  orange-brown 
fluid,  with  a  strong  astringent  taste. 


IRON.  665 

Liquor  Ferri  Perchloridi  (B.  P. )  and 

TINCTURA  FERRI  PERCHLORIDI  (B.  P.)  are  formed  by  diluting  the  strong 
liquor  with  3  times  as  much  water,  and  with  two  parts  of  water  and  one  of 
alcohol  respectively.  5-15  mins. 

The  chloride  is  used  as  a  styptic  either  as  the  Liquor  Fortis  (B.  P.)  or  in  a 
very  much  stronger  form,  prepared  by  allowing  the  crystals  to  deliquesce. 
A  plug  of  cotton-wool  steeped  in  the  solution  is  used  to  stop  bleeding  after 
the  extraction  of  teeth,  and  the  liquor  has  been  injected  into  the  uterus  in 
hemorrhage,  and  into  aneurisms  and  nsevi.  When  diluted  it  may  be  used 
as  a  gargle,  but  has  a  disagreeable,  inky  taste,  and  attacks  the  teeth.  The 
tincture  is  very  commonly  used  in  the  treatment  of  chlorosis.  It  ought  to  be 
taken  in  a  glass  of  water,  and  through  a  quill  or  glass  tube,  in  order  to  avoid 
injury  to  the  teeth. 

Liquor  Ferri  Nitratis  (B.  P.)  contains  3.3  per  cent,  of  iron.  5-15  mins. 
Used  as  an  astringent  to  a  limited  extent. 

Liquor  Ferri  Tersulphatis  (U.  S.  P.),  Liquor  Ferri  Persulphatis  (B.  P.),  a  so- 
lution of  ferric  sulphate  (Fe2(SO4)3),  is  used  only  for  the  preparation  of  other 
iron  salts. 

Liquor  Ferri  Subsulphatis  (U.  S.  P.),  Monsel's  solution,  an  aqueous  solu- 
tion of  basic  ferric  sulphate  of  variable  chemical  composition,  and  containing 
about  13.8  per  cent,  of  metallic  iron.  0.2-0.6  c.c.  (3-10  mins.).  Used  as  an 
astringent  gargle,  and  in  general  like  the  chloride. 

FERRI  SULPHAS  (U.  S.  P.,  B.  P.),  ferrous  sulphate  (FeSO4-f  7H2O),  large, 
pale,  bluish-green  crystals  with  a  saline,  astringent  taste,  soluble  in  water, 
insoluble  in  alcohol,  and  unstable  in  moist  air.  0.05-0.3  G.  (1-5  grs.). 

Ferri  Sulphas  Granulatus  (U.  S.  P.),  recrystallized  ferrous  sulphate  in  very 
small  crystals.  0.05-0.3  G.  (1-5  grs.). 

Ferri  Sulphas  Exsiccatus  (U.  S.  P.,  B.  P.),  dried  ferrous  sulphate  (2FeSO4 
+  3H2O),  ordinary  sulphate  from  which  most  of  Lie  water  of  crystallization 
has  been  driven  off  by  heat.  A  grayish-white  powder  resembling  the  ordi- 
nary sulphate  in  its  solubility.  0.03-0.2  G.  (J-3  grs.). 

Ferri  et  Ammonii  Sulphas  (U.  S.  P.),  ammonio-ferric  sulphate  or  ammonio- 
ferric  alum  (Fe2(NH4)2(SO4)4+24H2O),  is  a  double  salt  forming  pale  violet 
crystals  with  an  acid  astringent  taste — soluble  in  water,  not  in  alcohol, 
0.3-0.6  G.  (5-10  grs.). 

The  sulphate  of  iron  is  very  astringent,  though  less  so  than  the  ferric  salts. 
It  is  used  as  an  astringent  application  to  mucous  membranes,  such  as  the 
eye,  mouth,  urethra,  more  rarely  internally  in  anaemia,  although  it  is  less 
irritant  than  the  chloride. 

The  Pil.  Aloes  et  Ferri  (U.  S.  P.,  B.  P.),  which  is  used  very  largely  in 
amenorrhoea  and  in  chlorosis  with  constipation,  contains  dried  sulphate  of 
iron.  Dose,  B.  P.,  4-8  grs. 

Ferrum  (U.  S.  P. ,  B.  P.),  metallic  iron  in  the  shape  of  fine  wire  is  used  only 
to  form  other  preparations. 

FERRUM  REDUCTUM  (U.  S.  P.),  FERRUM  REDACTUM  (B.  P.),  reduced  iron, 
a  very  fine  grayish-black,  lustreless  powder,  without  taste,  insoluble  in  water 
or  alcohol,  soluble  in  acid.  It  consists  of  metallic  iron,  with  a  small  amount 
of  the  magnetic  oxide.  0.05-0.3  G.  (1-5  grs.). 

Trochiscus  Ferri  Redacti  (B.  P.),  each  contains  1  gr.  of  reduced  iron. 

FERRI  CARBONAS  SACCHARATUS  (U.  S.  P.,  B.  P.),  saccharated ferrous  car- 
bonate, is  formed  by  precipitating  ferrous  sulphate  with  sodium  bicarbonate 
(ammonium  carbonate,  B.  P.),  washing  the  precipitate  and  adding  sugar.  It 
contains  ferrous  carbonate  along  with  some  ferrous  sulphate  and  sodium  bi- 
carbonate (U.  S.  P.),  and  is  a  greenish-brown  powder,  which  rapidly  oxidizes 
in  the  air,  and  has  a  sweetish,  astringent  taste.  The  carbonate  is  a  very 
unstable  body,  and  on  keeping  is  slowly  transformed  to  ferric  hydrate 
(Fe2(OH)6).  The  sugar  is  added  in  order  to  retard  this  oxidation,  but  the 
carbonate  ought  not  to  be  dispensed  unless  it  is  of  recent  preparation.  0.6- 
2  G.  (10-30  grs.). 


666  THE  HEAVY  METALS. 

PILULE  FERRI  CARBONATIS  (U.  S.  P.),  PILULA  FERRI  (B.  P.),  ferruginous 
or  chalybeate  pills,  BLAUD'S  PILLS,  are  prepared  in  the  same  way,  by  the  ac- 
tion of  ferrous  sulphate  and  carbonate  of  potash  or  soda.  Sugar,  tragacanth 
and  glycerin  are  added  ;  they  ought  to  be  freshly  prepared  in  order  to  avoid 
the  formation  of  the  hydrate.  Each  pill  (U.  S.  P.)  contains  about  0.06  G. 
(1  gr.)  of  iron,  that  is,  5  grs.  contain  about  1  gr.  A  method  of  keeping  the 
carbonate  and  the  sulphate  apart  until  actually  swallowed  has  been  adver- 
tised, the  two  being  given  in  a  capsule,  but  being  separated  by  a  membrane 
which  is  dissolved  off  in  the  stomach.  This  same  effect  would  be  obtained  by 
giving  them  entirely  separate,  and  it  is  extremely  improbable  that  the  car- 
bonate is  formed  in  the  acid  contents  of  the  stomach.  1-5  pills  U.  S.  P. ,  5- 
15  grs.  B.  P. 

Massa  Ferri  Carbonatis  (U.  S.  P.),  Vallets'  Mass,  is  formed  by  the  action 
of  ferrous  sulphate  and  sodium  carbonate.  Sugar  and  honey  are  added  to 
the  precipitate  to  form  a  mass  of  the  proper  consistency  for  pills.  This 
preparation  has  never  enjoyed  the  popularity  of  Blaud's  pills  and  is  super- 
fluous. 0.2-0.3  G.  (3-5  grs.). 

MISTURA  FERRI  COMPOSITA  (U.  S.  P.,  B.  P.),  Griffith's  mixture,  is  formed 
by  mixing  ferrous  sulphate,  potassium  carbonate,  myrrh,  sugar,  spirits  of 
lavender  (nutmeg,  B.  P.)  and  rose  water.  The  ferrous  carbonate  (FeCO3)  is 
precipitated  and  the  mixture  has  therefore  to  be  shaken  before  taking,  and 
ought  to  be  freshly  prepared.  15-30  c.c.  (|-1  fl.  oz.). 

Reduced  iron  and  the  four  carbonate  preparations  are  used  exclusively  in 
the  treatment  of  ansemia.  They  are  practically  devoid  of  irritant  properties, 
and  are  among  the  best  of  all  the  iron  preparations  for  this  purpose.  The 
Blaud's  Pills  have  in  particular  a  well  merited  reputation  in  the  treatment 
of  chlorosis  and  of  chlorotic  amenorrhoea.  Another  preparation  used  for 
this  purpose  but  not  official  is  Ferrum  Dialysatum  in  which  a  considerable 
amount  of  iron  oxide  is  kept  in  a  semi-colloid  state  dissolved  in  a  minimum 
amount  of  the  chloride.  It  tastes  of  iron  but  is  not  astringent. 

Ferri  Hydroxidum  (U.  S.  P.),  ferric  hydrate,  or  hydroxide  (Fe2(OH)6),  a 
brownish-red,  pasty  mass,  insoluble  in  water  or  alcohol,  but  soluble  in  hydro- 
chloric acid,  is  used  almost  exclusively  in  the  treatment  of  arsenic  poisoning,  as  it 
is  supposed  to  retard  its  absorption  in  the  stomach.  It  ought  to  be  freshly  prepared, 
otherwise  it  forms  particles  which  combine  with  greater  difficulty  with  the  poison. 

Ferri  Hydroxidum  cum  Magnesia  (U.  S.  P.),  is  formed  by  precipitating  ferric 
sulphate  by  magnesia  and  is  used  in  arsenic  poisoning  and  known  as  the  arsenic 
antidote.  Both  of  these  preparations  have  to  be  given  freely  in  arsenic  poison- 
ing, at  least  15-20  G.  (£  oz.).  The  remedy  is  harmless  in  itself,  but  its  efficacy 
is  very  doubtful. 

Liquor  Ferri  Acetatis  (B.  P.),  an  aqueous  solution  of  the  acetate  (Fe2(C2H3O2)6), 
containing  about  31  per  cent,  of  the  salt  or  about  7.5  per  cent,  of  iron.  0.3-1 
c.c.  (5-15  mins.). 

Ferri  Citras  (U.  S.  P. ),  transparent,  garnet- red  scales  with  a  slight  iron  taste. 
0.05-0.3  G.  (1-5  grs.). 

Ferri  Phosphas  (B.  P.),  a  powder  containing  not  less  than  47  per  cent,  of  hy- 
drous ferrous  phosphate  (Fe3(PO4)28H2O),  with  ferric  phosphate  and  some  iron 
oxide.  It  is  a  slate-blue,  amorphous  powder,  insoluble  in  water.  5-10  grs. 

Syrupus  Ferri  Phosphatis  (B.  P.).  1  fl.  dr.  represents  1  gr.  of  anhydrous 
ferrous  phosphate.  £-1  fl.  dr. 

Ferri  Phosphas  Solubilis  (U.  S.  P.).  The  phosphate  of  iron  is  insoluble  in 
itself,  but  is  rendered  soluble  by  the  presence  of  sodium  citrate — thin,  green 
scales  with  a  saline  taste,  insoluble  in  alcohol.  0.1-0.5  G.  (2-8  grs.). 

Ferri  Pyrophosphas  Solubilis  (U.  S.  P.),  like  the  phosphate,  is  rendered 
soluble  by  sodium  citrate,  and  resembles  it  in  its  appearance  and  solubility. 
0.1-0.5  G.  (2-8  grs.). 

Ferri  Hypophosphis  (U.  S.  P.)  (Fe2(PH2O2)6),  a  white  powder,  odorless 
and  nearly  tasteless,  almost  insoluble  in  water,  but  dissolved  by  solutions  of 
the  alkali  citrates.  0.3-1  G.  (5-15  grs.),  in  pill. 


IRON.  667 

Pilultz  Ferri  lodidi  (U.  S.  P.),  each  contains  0.04  G.  of  iron.     1-2  pills. 

Syrupy s  Ferri  lodidi  (U.  S.  P.,  B.  P.)  contains  about  1.8  per  cent,  of  iron. 
2-4  c.c.  (i-1  fl.  dr.). 

Ferri  Arsenas  (B.  P.),  iron  arsenate,  consists  of  ferrous  arsenate 
(Fe3(AsO4)2,  6H2O),  with  ferric  arsenate  and  some  iron  oxide,  and  forms  a 
tasteless,  amorphous  powder  of  a  greenish  color,  insoluble  in  water,  TS~i  gr- 

These  preparations  have  all  been  prescribed  to  a  greater  or  less  extent  in 
the  treatment  of  anaemia,  the  lactate,  phosphate  and  pyrophosphate  being 
perhaps  more  widely  used  than  the  others.  It  is  needless  to  repeat  that  the 
valerianate  is  not  of  greater  value  in  hysteria  than  the  other  preparations,  as 
valerianic  acid  is  useless  in  this  condition.  The  iodide  has  been  advised  in 
order  to  combine  the  effects  of  iodide  and  iron,  but  the  iodide  given  in  this 
form  is  in  much  smaller  quantity  than  that  found  necessary  in  the  iodide  of 
potassium  treatment,  and  it.  seems  open  to  question  whether  the  improvement 
is  not  due  to  the  iron  only.  The  hypophosphite  is  also  used  in  cachexia,  in 
order  to  combine  the  hypophosphite  and  the  iron  effects. 

Ferri  et  Quininse  Citras  (U.  S.  P.,  B.  P.),  thin  scales  of  a  reddish-brown 
color,  and  of  a  bitter,  iron  taste,  slowly  soluble  in  water,  partially  soluble  in 
alcohol,  containing  11.5  percent,  of  quinine  and  14.5percent.  of  iron  U.  S.  P. 
0.3-0.6  G.  (5-10  grs.). 

Ferri  et  Quininss  Citras  Solubilis  (U.  S.  P.),  thin  scales  of  a  greenish  color 
and  of  a  bitter,  iron  taste,  easily  soluble  in  water,  only  partially  in  alcohol. 
It  contains  the  same  amount  of  iron  and  quinine  as  the  ordinary  preparation. 
0.3-0.6  G.  (5-10  grs.). 

Ferri  et  Strychninse  Citras  (U.  S.  P.),  thin,  transparent  scales  of  garnet-red 
or  yellowish-brown  color,  readily  soluble  in  water,  containing  about  1  per 
cent,  of  strychnine  and  about  16  per  cent,  of  iron.  0.1-0.3  G.  (2-5  grs.). 

Syrupus  Ferri,  Quininse  et  Strychninse  Phosphatum  (U.  S.  P.),  Syrupus  Ferri 

Phosphatis  cum  Quinina  et  Strychnina  (B.  P.).      2-4  c.c.  ($-1  fl.  dr.). 

Glyceritum  Ferri,  Quinines  et  Strychnine  Phosphatum  ( U.  S.  P. ).  1  c.  c.  ( 15  mins. ). 

Elixir  Ferri,  Quinince  et  Strychnine  Phosphatum  (U.  S.  P.).     4  c.c.  (1  fl.  dr.). 

Ferri  et  Ammonii  Citras  (U.  S.  P.,  B.  P.),  thin  garnet-red  scales  with  an 
acid,  iron  taste,  soluble  in  water  and  containing  16  per  cent.  iron.  0.3-0.6 
G.  (5-10  grs.). 

Ferri  et  Ammonii  Tartras  (U.  S.  P.),  thin,  transparent,  garnet-red  scales, 
very  soluble  in  water  and  containing  about  17  per  cent,  of  iron.  0.3-0.6  G. 
(5-10  grs.). 

Ferri  et  Potassii  Tartras  (U.  S.  P.),  Ferrum  Tartar  atum  (&.  P.)  resembles  the 
last  preparation,  but  contains  only  about  15  per  cent,  of  iron.  0.3-0.6  G. 
(5-10  grs.). 

Liquor  Ferri  et  Ammonii  Acetatis  (U.  S.  P.),  Basham's  mixture,  contains 
only  a  very  small  proportion  of  iron,  along  with  acetic  acid,  ammonium 
acetate,  aromatic  elixir  and  glycerin.  15-30  c.c.  (J-l  fl.  oz.). 

Vinum  Ferri  (B.  P.).     1-4  fl.  drs. 

Vinum  Ferri  Amarum  (U.  S.  P.).      8-15  c.c.  (2-4  fl.  drs.). 

Vinum  Ferri  Citratis  (B.  P.),  Vinum  Ferri  (U.  S.  P.).     4-15  c.c.  (1-4  fl.  drs.). 

The  two  wines  of  iron  of  the  U.  S.  P.  are  practically  identical  except  that 
the  first  contains  the  citrate  of  iron  and  quinine,  the  second,  the  citrate  of 
iron  and  ammonium.  Each  is  made  up  with  tincture  of  sweet  orange  peel, 
syrup  and  white  wine.  The  iron  wine  of  the  B.  P.  is  formed  by  dissolving 
iron  in  sherry  wine,  the  citrate  of  iron  wine  by  dissolving  the  citrate  in 
orange  wine. 

The  double  salts  of  iron  (scale  preparations)  and  the  wines  are  used  to 
some  extent  in  chlorosis,  but  more  frequently  in  convalescence  from  acute 
fevers,  which  is  often  attended  by  anemia :  in  these  cases  the  iron  wines 
are  often  of  considerable  value.  The  double  salts  are  not  so  liable  to  disturb 
the  digestion  as  the  other  soluble  preparations  of  iron,  but  are  not  superior 
to  the  carbonate  preparations  and  the  reduced  iron  in  this  respect. 


668  THE  HEAVY  METALS. 

Iron  is  contained  in  many  mineral  waters,  which  are  therefore  advised  in 
cases  of  anaemia.  It  is  generally  in  the  form  of  the  carbonate,  which  is  dis- 
solved by  the  excess  of  carbonic  acid  present,  but  becomes  oxidized  to 
the  insoluble  ferric  hydrate  in  the  air.  The  amount  of  iron  contained  is 
small,  seldom  being  more  than  0.1  G.  per  litre,  but  the  treatment  of 
chlorosis  is  unquestionably  aided  by  change  of  scene  and  in  particular  by  the 
high  elevations  at  which  many  of  these  springs  are  situated,  so  that  the  suc- 
cess of  treatment  with  these  iron  waters  is  perfectly  intelligible.  Bathing  in 
iron  water  has  no  further  action  on  the  blood  than  ordinary  baths,  as  no 
iron  is  absorbed. 

Many  Proteid  Compounds  of  iron  have  been  introduced  into  therapeutics 
in  the  last  few  years,  but  few  of  them  need  be  mentioned,  as  a  large  number 
of  them  promise  to  be  relegated  to  merited  oblivion  in  the  near  future.  The 
albuminate  of  iron  and  the  peptonate  of  iron  are  generally  prepared  by  the 
action  of  the  chloride  on  egg  albumin  or  on  peptone,  and  vary  very  consid- 
erably in  the  percentage  of  iron  contained.  In  most  of  them  the  albu- 
minate or  peptonate  is  accompanied  by  more  or  less  perchloride  and  oxide. 
These  preparations  are  not  "organic  "  iron  in  the  sense  denned  on  page  659, 
for  the  iron  can  be  split  off  easily,  and  is  precipitated  by  sulphides  almost 
as  readily  as  the  ordinary  salts.  The  albumiuate  and  peptonate  possess  no 
advantage  over  the  usual  preparations,  unless  they  prove  less  irritant  to  the 
stomach,  and  of  this  there  is  no  satisfactory  evidence.  Soluble  peptonateand 
albuminate  of  iron  are  put  on  the  market  by  a  number  of  manufacturers. 

Schmiedeberg  found  in  the  liver  an  iron  compound  which  does  not  seem 
to  resemble  the  ordinary  salts,  for  it  is  only  blackened  by  sulphides  after 
sometime,  and  in  other  ways  shows  resemblances  to  the  "organic  iron," 
such  as  the  hsematogen  of  the  yolk  of  egg.  It  would  seem  to  stand  midway 
between  the  ordinary  dissociable  salts  and  hemoglobin,  for  it  reacts  to 
ammonium  sulphide  more  tardily  than  the  former,  while  the  latter  is  not 
affected  by  this  reagent.  Schmiedeberg  named  this  compound,  which  is 
an  iron -containing  proteid,  Ferratin.  He  attempted  to  form  a  similar  sub- 
stance synthetically  from  the  white  of  egg,  and  obtained  a  body  containing 
6-8  per  cent,  of  iron,  which  reacted  similarly  with  sulphide,  and  which  he 
failed  to  dissociate  by  electrolysis.  Believing  it  to  be  identical  with  the 
hepatic  ferratin,  he  advised  its  use  in  chlorosis  as  being  a  natural  food  iron. 
It  is  impossible  to  state  from  these  reactions,  however,  that  the  two  sub- 
stances— the  hepatic  and  the  artificial  ferratin — are  identical,  and,  in  fact, 
Macallum  finds  that  the  former  fails  to  give  the  haematoxylon  test,  while  the 
latter  yields  it  readily. 

Artificial  ferratin  is  partially  decomposed  in  the  stomach  into  ordinary 
inorganic  salts,  but  there  seems  reason  to  believe  that  it  is  absorbed  more 
easily  than  the  usual  preparations,  and  it  is  not  irritant  to  the  stomach  and 
does  not  often  give  rise  to  dyspepsia.  On  the  whole,  ferratin  seems  a  good 
preparation  for  use  in  chlorosis,  but  possesses  no  such  specific  virtues  as  have 
been  attributed  to  it  by  enthusiastic  advocates,  and  it  has  the  disadvantage 
of  being  very  much  more  expensive  than  most  other  preparations.  It  is 
given  in  powder  or  pill,  or  in  solution  as  a  sodium  compound,  in  quantities 
of  0.5-1.5  G.  (8-20  grs.)  per  day. 

Carniferrin  is  an  iron  compound  of  carniphosphoric  (phosphosarkinic) 
acid,  which  is  obtained  from  beef  extract.  It  contains  35  per  cent,  of  iron, 
and  seems  to  bear  the  same  relation  to  the  inorganic  salts  and  to  haemo- 
globin as  artificial  ferratin,  for  while  it  reacts  slowly  to  sulphide,  it  gives  the 
haematoxylon  test.  It  has  been  highly  recommended  in  chlorosis,  as  it  does 
not  irritate  the  stomach  and  is  rapidly  absorbed.  It  is  given  in  doses  of 
0.5  G.  (8  grs.)  three  times  a  day  in  powder,  and  like  ferratin,  is  soluble  in 
alkaline  solutions. 

The  hsematogen  of  the  yolk  of  egg,  another  organic  iron  of  the  same  type 
as  ferratin  and  carniferrin,  is  obtained  in  too  small  quantity  to  be  available 
for  therapeutic  use,  but  seems  to  be  absorbed  readily. 


IEON.  669 

Other  proteid  compounds  which  have  been  advised  are  formed  from  yolk 
of  egg  or  from  casein,  by  the  addition  of  iron  salts. 

Blood  has  been  used  in  therapeutics  by  uncivilized  peoples  since  time 
unknown,  and  has  also  been  recommended  in  modern  medicine  in  the 
treatment  of  chlorosis,  in  which  it  is  administered  by  the  mouth,  and  also 
hypodermically,  though  the  latter  method  is  difficult  to  carry  out  aseptically. 
Haemoglobin  has  also  been  advertised  largely  of  late  years  in  a  more  or  less 
impure  form.  In  the  stomach,  haemoglobin,  whether  contained  in  blood  or 
as  crystals,  is  changed  to  haematin ;  Abderhalden  found  that  both  haemo- 
globin and  hsematin  are  absorbed  and  lead  to  an  increase  in  the  haemoglo- 
bin of  the  blood.  Hsemol  and  hsemogollol  are  prepared  from  blood  by  agitat- 
ing it  with  zinc  and  with  pyrogallol  respectively,  and  have  been  strongly 
recommended  by  their  discoverer,  Robert,  and  by  some  clinicians,  but  have 
been  found  by  others  of  less  value  than  the  old  inorganic  salts. 

The  ' t  organic ' '  iron  preparations  therefore  seem  to  have  little  to  recom- 
mend them  as  superior  to  the  * '  inorganic, ' '  except  that  ferratin  and  carni- 
ferrin  are  probably  more  rapidly  absorbed,  and  are  less  liable  to  cause 
dyspepsia  than  many  of  the  older  salts.  Where  there  is  special  difficulty  in 
administering  the  more  commonly  used  forms,  these  two  may  be  substituted 
for  them  with  advantage,  but  they  seem  to  be  unnecessary  in  ordinary  cases. 
In  regard  to  the  other  preparations  mentioned,  further  and  impartial  inves- 
tigation is  required  before  their  place  in  therapeutics  can  be  determined. 

BIBLIOGRAPHY. 

Meyer  u.  Williams,     Arch.  f.  exp.  Path.  u.  Pharm.,  xiii.,  p.  70. 

Robert.     Ibid.,  xvi.,  p.  361. 

Hamburger.     Zts.  f.  phys.  Chem.,  ii.,  p.  191  ;  iv.,  p.  248. 

Bunge.     Ibid.,  ix.,  p.  49  ;  xiii.,  p.  399  ;  xvi.,  p.  173  ;  xvii.,  p.  63. 

Hdusermann.     Ibid.,  xxiii.,  p.  555. 

Bunge,  Quincke.     Cong.  f.  inn.  Med.,  1895,  p.  133. 

Marfori.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxix.,  p.  212. 

Schmiedeberg.     Ibid.,  xxxiii.,  p.  101. 

Gottlieb.     Ibid.,  xxvi.,  p.  139.     Zts.  f.  phys.  Chem.,  xv.,  p.  371. 

Jakobj.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxviii.,  p.  256. 

Socin.     Zts.    f.  phys.  Chem.,  xv.,  p.  93. 

Molisch.     Sitzungber.  Wien.  Akad.,  ciii.,  1894,  Abt.  i.,  p.  554. 

Kunkel     Pfliiger's  Arch.,  1.,  p.  1  ;  Ixi.,  p.  595. 

Stockman.  Brit.  Med.  Journ.,  1893,  i.,  p.  881.  Journ.  of  Phys.,  xviii.,  p.  484  ;  xxi., 
p.  55  (with  Greig). 

Macallum.     Journ.  of  Phys.,  xvi.,  p.  268  ;  xxii.,  p.  92. 

Woltering.     Ztschr.  f.  phys.  Chem.,  xxi.,  p.  186. 

Hall.     Arch.  f.  Anat.  u.  Phys.,  1894,  p.  455  ;  1896,  p.  49. 

Pohl.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxv.,  p.  65. 

Gaute.  Deutsch.  med.  Woch.,  xxii.,  pp.  289,  373  (1896).  Zts.  f.  Biol.,  xxxv.,  p. 
377. 

Hochhaus  u.  Quincke.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii.,  p.  159. 

Damaskin,  Kumberg,  Busch,  Stender,  Anselm,  Samojloff.  Arb.  a.  d.  pharm.  Instit.  zu 
Dorpat,  vii.,  viii.,  ix. 

Cloetta.  Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii.,  p.  69;  xxxviii.,  p.  161  ;  xliv., 
p.  363. 

Hofmann.     Virchow's  Arch.,  cli.,  p.  488. 

Filippi.     Ziegler's  Beitrage  zur  path.  Anat.,  xvi.,  p.  462. 

Morner.     Zts.  f.  phys.  Chem.,  xviii.,  p.  13. 

Buzdygan.     Wien.  klin.  Woch.,  1897,  p.  713. 

Voit.     Zts.  f.  Biol.,  N.  F.,  xi.,  p.  387  (1893). 

Glaevecke.     Arch.  f.  exp.  Path.  u.  Pharm.,  xvii.,  p.  466. 

Baumann.     Journ.  of  Phys.,  xxix.,  p.  18. 

Tartakowsky.     Pfliiger's  Arch.,  ci.,  p.  423. 

V.  Noorden.     Berl.  klin.  Woch.,  1895,  p.  181. 
Hari.     Arch.  f.  Verdauungskrank. ,  iv.,  p.  160. 
Abderhalden.     Ztschr.  f.  Biologic,  xxxix.,  pp.  113,  193,  487. 

Mulkr.     Virchow's  Arch.,  clxiv.,  p.  436. 


670  THE  HEAVY  METALS. 

IV.     LEAD. 

Lead  is  used  to  some  extent  in  therapeutics,  but  its  chief  interest 
from  a  medical  point  of  view  lies  in  the  frequency  with  which  it  gives 
rise  to  chronic  poisoning,  and  in  the  diversity  of  the  symptoms  pre- 
sented in  that  condition. 

Solutions  of  lead  salts  precipitate  albumin,  and  the  precipitate  is 
more  dense  and  heavy  than  that  of  mercury,  and  less  soluble  in  excess 
of  the  salt.  This  precipitate  is  formed  when  lead  solutions  are  applied 
to  the  mucous  membranes,  and  protects  them  from  the  penetration  of 
the  metal,  so  that  lead  is  one  of  the  least  corrosive,  and  one  of  the  most 
astringent  of  the  heavy  metals.  This  absence  of  corrosion  is  only  in 
part  due  to  the  character  of  the  precipitate,  for  lead  forms  insoluble 
and  therefore  non-irritant  salts  with  two  of  the  most  corrosive  acids, 
hydrochloric  and  sulphuric  acids.  The  soluble  nitrate  of  lead  is 
comparatively  irritating  because  it  is  readily  dissociated  and  also  be- 
cause the  nitric  acid  formed  by  its  contact  with  proteid  is  itself  corro- 
sive. The  only  soluble  salts  which  are  largely  used  are  the  acetates, 
and  these  are  slowly  dissociated  and  the  acid  is  only  slightly  active,  so 
that  the  astringent  metallic  ion  alone  comes  into  play. 

Symptoms.  —  In  ordinary  therapeutic  doses,  the  acetate  of  lead 
(sugar  of  lead)  has  a  sweetish,  metallic  taste  followed  by  a  feeling  of 
astringeucy,  and  induces  no  symptoms  except  constipation.  The  stools 
after  lead  are  often  said  to  be  dark  in  color  from  the  sulphide  formed 
in  the  intestine,  but  this  does  not  seem  to  be  the  general  rule.  Prob- 
ably little  lead  is  absorbed  from  an  ordinary  dose  of  the  acetate ;  at 
any  rate  no  symptoms  arise  from  the  general  action  of  the  metal  ab- 
sorbed. 

Lead  acetate  solutions  applied  to  the  skin  have  no  effect,  but  mucous 
membranes,  or  exposed  tissues,  such  as  ulcers,  are  covered  with  a  thin 
pellicle  of  albuminate,  which  serves  to  protect  them  from  irritation, 
and  thus  promotes  their  healing. 

When  very  large  quantities  of  acetate  are  swallowed,  particularly  if 
in  a  concentrated  form,  they  give  rise  to  the  ordinary  symptoms  of  irri- 
tant poisoning,  nausea,  vomiting,  pain  in  the  abdomen,  violent  purg- 
ing or  sometimes  constipation,  blood  in  the  vomited  matter  and  stools, 
great  thirst,  weakness,  and  collapse.  In  some  instances  in  which  the 
patients  recovered  from  these  symptoms,  they  subsequently  suffered 
from  chronic  lead  poisoning,  but  apart  from  these,  nothing  in  the  course 
of  acute  lead  poisoning  suggests  the  absorption  of  the  metal,  all  the 
symptoms  being  obviously  due  to  the  local  effects  on  the  stomach  and 
bowel,  and  to  the  consequent  collapse.  In  fact  the  effects  of  a  sudden 
absorption  of  lead  in  man  are  unknown. 

In  animals  also,  some  difficulty  has  been  met  in  inducing  the  symptoms 
due  to  the  action  of  large  quantities  of  lead  in  the  tissues,  because  most 
forms  of  lead  injected  into  the  vessels  precipitate  the  proteids  of  the  blood 
and  cause  embolism,  while,  on  the  other  hand,  only  local  symptoms  can  be 
induced  by  its  administration  by  the  mouth.  Harnack  investigated  this 


LEAD.  671 

point  by  injecting  salts  of  lead-triethyl,  in  which  the  metal  is  not  contained 
in  a  dissociable  form,  but  which  is  decomposed  in  the  tissues  and  then  gives 
rise  to  lead  symptoms.  In  this  way  he  hoped  to  be  able  to  elucidate  the 
symptoms  of  chronic  lead  poisoning,  but  his  results  have  not  been  of  much 
value  for  this  purpose,  although  they  are  of  some  interest.  In  the  frog  he 
found  that  his  compound  produced  general  paralysis,  which  he  ascribed  to 
action  on  the  muscles,  but  which  Wyss  later  stated  to  be  due  to  action  on  the 
central  nervous  system.  Harnack  describes  the  muscles  as  being  easily 
fatigued,  and  gives  some  further  peculiarities  induced  by  lead  in  them,  but 
Wyss  found  in  apparently  equally  satisfactory  experiments  that  the  muscles 
were  practically  unaffected  at  death.  In  the  dog  large  doses  of  lead  injected 
into  a  vein  induced  weakness  and  paralysis,  violent  diarrhoea,  chorea-like 
movements,  tremors,  which  often  assume  the  appearance  of  true  convulsions, 
and  ataxia.  The  diarrhoea  was  attended  by  severe  colic,  and  both  of  these 
symptoms  were  removed  by  atropine.  It  would  therefore  appear  that  the 
colic  is  here  due  to  nervous  influences,  and  not  to  the  muscle  of  the  intestine 
being  immediately  acted  upon,  for  atropine  paralyzes  only  the  terminations 
of  nerves.  The  diarrhoea  Harnack  found  to  be  due  to  violent  contrac- 
tions of  the  intestinal  walls,  which  maintained  a  certain  degree  of  contraction 
even  when  no  peristaltic  wave  was  passing.  This  action  of  lead  upon  the 
intestine  is  of  interest,  because  it  bears  a  close  relation  to  the  colic  observed 
in  chronic  lead  poisoning  in  man,  although  here  there  is  generally  con- 
stipation, and  also  because  it  connects  lead  with  the  other  heavy  metals, 
all  of  which  have  more  or  less  specific  action  on  the  intestine.  The  ataxia 
and  other  brain  symptoms  also  have  their  counterpart  in  the  brain  symptoms 
of  chronic  poisoning  in  man. 

A  single  dose  of  a  lead  salt  does  not  generally  give  rise  to  any  symp- 
toms which  would  indicate  the  absorption  of  the  metal,  but  the  con- 
tinued ingestion  of  small  quantities  by  way  of  the  stomach,  or  by 
inhalation  by  the  lungs,  induces  chronic  poisoning,  which  can  be  ex- 
plained only  by  its  absorption.  There  seems  some  reason  to  believe 
that  lead  is  absorbed  from  the  unbroken  skin,  though  it  is  possible  that 
some  of  the  metal  was  carried  to  the  mouth  and  swallowed  with  the 
food  in  the  cases  on  which  the  statement  is  founded.  Lead  is  appar- 
ently Absorbed  more  rapidly  than  most  of  the  metals  except  mercury, 
and  remains  lodged  in  the  tissues  a  long  time,  the  excretion  taking 
place  only  very  slowly.  It  is  found  in  most  organs  in  cases  of  poison- 
ing, particularly  in  the  liver  and  kidney.  It  is  Excreted  in  the  urine, 
the  bile,  the  secretion  of  the  intestinal  epithelium,  and  in  milk  and 
saliva.  It  is  still  disputed  whether  it  is  eliminated  by  the  skin  glands, 
or  whether  the  lead  often  seen  on  the  skin  in  cases  of  poisoning  is  not 
simply  deposited  there  as  dust  from  the  air. 

Chronic  Lead  Poisoning  is  the  commonest  of  all  forms  of  metallic 
poisoning,  and  at  the  same  time  one  of  the  most  insidious.  It  is  al- 
ways accidental,  and  although  it  is  most  common  in  workers  in  lead, 
may  occur  in  persons  who  are  not  apparently  liable  to  come  in  contact 
with  the  metal.  There  is  no  question  that  some  people  are  much  more 
susceptible  to  lead  than  others.  Anemia  and  weakness  from  any  cause 
are  generally  believed  to  predispose  to  the  disease,  women  and  children 
are  more  liable  to  it  than  men,  and  alcoholism  and  previous  lead  in- 
toxication increase  the  tendency  to  the  attack.  Relapses  are  very 
common,  and  may  occur  years  after  the  first  symptoms,  even  although 


672  THE  HEAVY  METALS. 

there  has  been  no  further  exposure  in  the  interval.  Lead  smelters, 
workers  in  white  lead  factories,  painters,  plumbers,  electricians,  and 
typesetters  are  liable  to  lead  poisoning  from  continually  handling  the 
metal ;  but  other  trades  are  not  exempt  from  it,  and  sometimes  the 
channels  by  which  it  gains  entrance  to  the  body  are  very  obscure. 
Some  of  the  more  common  causes  of  poisoning  are  lead  water-pipes  or 
cooking  utensils,  lead  used  to  close  tins  of  meat  or  fruit,  and  lead  in 
hair  dyes.  Formerly  a  common  source  of  poisoning  was  wine  and 
cider  to  which  lead  had  been  added  to  reduce  the  acidity.  A  consider- 
able number  of  cases  of  poisoning  have  been  recorded  from  the  use  of 
lead  preparations  as  abortifacients. 

The  symptoms  of  chronic  lead  poisoning  vary  greatly  in  different 
cases,  sometimes  only  one  or  two  organs  being  attacked,  in  others  the 
whole  economy  appearing  involved  in  the  disorder.  The  symptoms 
may  be  divided  into  groups  for  convenience,  but  it  is  to  be  noted  that 
many  of  these  appear  to  be  closely  inter-connected,  and  that  in  many 
cases  it  is  impossible  to  decide  whether  a  set  of  symptoms  is  due  to 
direct  action  upon  a  single  organ,  or  to  the  simultaneous  disease  of 
several. 

The  Mouth,  Stomach  and  Digestion  very  often  give  early  indications 
of  lead  poisoning.  The  patient  complains  of  loss  of  appetite,  nausea, 
constipation,  wasting,  a  metallic  taste  and  foetid  breath,  and  a  blue- 
black  line  is  seen  along  the  margin  of  the  teeth  where  they  enter  the 
gums.  This  "  lead  line  "  is  due  to  the  precipitation  of  lead  sulphide 
by  the  hydrogen  sulphide  produced  by  the  action  of  bacteria,  and  it  is 
often  absent,  especially  where  the  teeth  are  not  carious  and  are  kept 
clean.  The  metallic  taste  seems  due  to  the  excretion  of  lead  in  the 
saliva,  and  the  loss  of  appetite  may  arise  from  the  same  cause.  These 
symptoms  may  be  produced  in  animals  also.  Virchow  and  Maier 
found  in  one  case  in  man  the  gastric  epithelium  in  a  state  of  fatty  de- 
generation, and  proliferation  of  the  connective  tissue  of  the  mucous 
membrane. 

Another  early  symptom  is  Anaemia,  which  may  be  due  in  part  to  the 
malnutrition,  but  is  attributed  mainly  to  an  abnormal  destruction  of 
the  red  cells  of  the  blood ;  the  white  corpuscles  are  increased  in  many 
cases  but  not  in  all.  It  is  often  accompanied  by  jaundice,  with  the 
highly  pigmented  urine  and  other  symptoms  which  usually  follow  the 
liberation  of  large  quantities  of  haemoglobin  from  the  breaking  up  of 
red  cells.  It  is  stated  that  the  red  blood-cells  often  contain  granules 
staining  with  basophile  dyes  and  indicating  incomplete  disappearance 
of  the  nucleus  ;  this  change  may  present  itself  before  any  other  symp- 
tom. The  anaemia  is  often  very  marked,  and  is  sometimes  the  chief  or 
only  symptom  of  lead  poisoning  ;  according  to  some  authorities,  it  is 
present  in  a  greater  or  less  degree  in  the  majority  of  white-lead  work- 
ers, and  it  leads  to  weakness,  languor,  and  in  young  women  often  to 
amenorrhoaa.  Abortion  is  very  often  met  with  in  lead  poisoning,  and 
in  women  employed  in  lead  works  who  do  not  show  any  marked  symp- 
toms of  disease.  The  children  of  parents  suffering  from  lead  are  often 


LEAD.  673 

weak  and  undersized,  and  a  very  large  proportion  of  them  die  in  early 
infancy. 

One  of  the  commonest  symptoms  is  Lead  Colic,  painters'  colic,  colica 
saturnina  or  colica  Pictonum.  This  generally  sets  in  suddenly,  and  is 
accompanied  in  most  cases  by  obstinate  constipation,  in  a  very  small 
proportion  by  diarrhoaa.  Paroxysms  of  the  most  acute  agony  are  fol- 
lowed by  intervals  of  comparative  freedom  from  pain,  but  in  these  in- 
tervals some  tenderness  of  the  abdomen  may  be  complained  of,  while 
during  the  attack  pressure  generally  relieves  the  pain.  The  colic  lasts 
for  several  days,  or  a  week,  and  then  disappears,  but  is  liable  to  return 
at  intervals.  The  abdomen  is  generally  hollow,  retracted  and  hard, 
and  during  the  acute  spasms  the  patient  often  gains  some  relief  by  lying 
on  his  face  with  the  fists  pressed  against  the  umbilical  region,  to  which 
the  pain  is  usually  referred.  Vomiting  is  frequently  present,  the  pulse 
is  slow  and  very  hard,  especially  during  the  acute  crises,  while  the 
respiration  may  be  accelerated.  The  urine  is  scanty,  and,  according 
to  Stokvis  and  Nakorai,  contains  hsematoporphyrin. 

The  cause  of  lead  colic  is  evidently  spasm  of  the  intestine,  which  is 
generally  attributed  to  action  on  the  nervous  ganglia  of  the  walls.  It 
can  be  induced  in  animals,  and  according  to  Harnack,  is  relieved  by 
atropine,  which  would  support  the  belief  that  it  is  of  nervous  origin. 
The  blood-pressure  is  raised  in  man,  not  only  during  the  spasms,  but 
also  in  the  intervals.  This  contraction  of  the  vessels  and  the  slowing 
of  the  pulse  is  often  said  to  be  reflex  from  the  pain,  but  this  seems  to 
be  disproved  by  the  fact  that  it  remains  during  the  intervals.  Some 
writers  have  therefore  regarded  the  colic  and  its  attendant  symptoms 
as  due  to  a  vascular  spasm,  and  have  supported  this  by  showing  that 
nitrite  of  amyl,  which  dilates  the  vessels,  also  relieves  the  colic. 

On  the  whole,  the  colic  appears  to  be  of  nervous  origin,  but  whether 
the  focus  of  disease  lies  in  the  wall  of  the  intestine,  in  the  nerves 
leading  to  it,  or  in  the  central  nervous  system,  it  is  impossible  to  de- 
termine at  present. 

Another  common  result  of  chronic  lead  poisoning  is  Paralysis,  lead 
or  painters'  palsy,  paralysis  saturnina,  which  is  almost  invariably 
limited  to  certain  groups  of  muscles,  the  extensors  of  the  forearm. 
It  is  bilateral  in  the  great  majority  of  cases,  but  sometimes  involves 
only  one  arm.  The  affection  generally  begins  in  the  middle  and  ring 
fingers,  which  cannot  be  extended,  then  spreads  to  the  index  and  little 
finger,  and  afterwards  to  the  thumb  and  wrist.  The  fingers  remain 
flexed  and  later  the  wrist  is  similarly  affected,  so  that  the  condition  is 
often  known  as  wrist-drop.  Even  after  all  the  other  muscles  of  the  ex- 
tensor surface  of  the  forearm  are  involved,  the  supinator  longus  remains 
normal  as  a  general  rule.  The  muscles  affected  atrophy  rapidly,  and 
in  old  cases  contracture  of  the  flexor  muscles  sets  in,  when  the  limb 
becomes  immovable  and  has  a  characteristic  claw-like  appearance. 
More  rarely  other  regions  are  affected,  such  as  the  laryngeal  muscles  (in 
the  horse),  the  external  rectus  of  the  eye,  or  the  muscles  of  the  leg.  In 
rabbits  and  guinea-pigs  several  observers  have  succeeded  in  inducing 
43 


674  THE  HEAVY  METALS. 

paralysis  of  the  hind  limbs,  and  the  legs  are  said  to  be  affected  very 
often  in  young  children.  When  paralysis  is  complete,  the  induced 
electric  current  fails  to  cause  contraction,  whether  it  is  applied  to  the 
muscle  or  to  the  nerve,  but  the  galvanic  shock  induces  an  abnormally 
strong  contraction  when  it  is  passed  through  the  muscle,  the  make 
shock  having  more  effect  than  the  break  ;  the  contraction  is  more  pro- 
longed, the  relaxation  slower  than  in  normal  muscles.  This  reaction 
of  degeneration  is  said  to  occur  in  the  other  muscles  in  lead  poisoning, 
even  when  no  paralysis  can  be  detected  in  them.  The  cause  of  lead 
palsy  is  still  undecided,  for  while  in  some  cases  there  is  undoubtedly  a 
peripheral  neuritis  and  nerve  degeneration,  and  no  anatomical  lesion 
of  the  spinal  cord,  yet  in  others  very  distinct  degeneration  of  the  cord, 
particularly  of  the  cells  of  the  anterior  horn,  has  been  observed.  Al- 
though the  majority  of  pathologists  at  the  present  time  are  of  the 
opinion  that  the  lesion  is  a  peripheral  neuritis,  and  that  the  degenera- 
tion of  the  cord  is  either  a  consequence  of  this,  or  is  perhaps  an  en- 
tirely independent  lesion,  some  authorities  hold  that  the  focus  of  dis- 
ease is  situated  in  the  cord,  and  that  the  neuritis  is  merely  an  extension 
of  the  process.  They  explain  the  absence  of  visible  changes  of  the 
cord  in  some  cases  by  supposing  that  the  function  of  the  cell  is  de- 
stroyed by  the  poison,  without  actual  anatomical  lesion.  A  third  view 
which  was  held  formerly,  but  has  been  abandoned  except  by  a  very 
few,  is  that  the  original  lesion  is  in  the  muscles.  Peripheral  neuritis 
has  been  elicited  repeatedly  in  animals. 

Local  Anaesthesia  is  also  observed  occasionally,  though  much  more 
rarely  than  paralysis.  It  is  generally  sudden  in  its  onset,  but  may  be 
preceded  by  numbness  or  tickling  of  the  skin,  and  generally  lasts  only 
one  or  two  weeks,  when  sensation  returns  again  to  the  part. 

Lead  Arthralgia  is  more  commonly  observed,  perhaps  because  it  is 
so  much  more  evident.  It  consists  in  sharp  lancinating  or  boring 
pains  in  the  joints,  bones,  or  the  flexor  muscles  around  the  joints,  the 
intensity  of  the  pain  being  comparable  only  to  that  of  lead  colic.  It 
sets  in  suddenly,  usually  in  the  night,  and  generally  disappears  as  sud- 
denly. This  symptom  is  not  in  any  way  dependent  on  the  gout  which 
is  often  induced  by  lead  poisoning,  and  its  explanation,  like  that  of 
the  anaesthesia,  is  quite  unknown. 

Lead  Amblyopia,  or  blindness,  is  one  of  the  rarer  affections.  The 
sight  may  be  lost  completely,  or  may  only  be  dim,  and  the  onset  may 
be  sudden  or  gradual.  In  some  cases  the  ophthalmoscope  gives  no 
clue  to  the  cause  of  the  blindness,  in  others  an  acute  papillitis  is  made 
out.  Stood  ascribes  the  amblyopia  to  several  causes,  which  may  each 
give  rise  to  it  separately  or  may  act  together.  The  first  of  these  is 
a  neuritis  of  the  optic  nerve  in  the  eye,  which  gives  distinct  ophthal- 
moscopic  appearances.  In  the  second  the  neuritis  may  be  descend- 
ing or  retrobulbar,  and  may  induce  little  visible  change,  while  the 
third  cause  of  blindness  may  be  uremia  with  an  effusion  into  the  optic 
sheath,  and  a  fourth  is  albuminuric  retinitis,  these  two  last  forms 
being  due  not  to  a  direct  action  on  the  nerve,  but  to  the  nephritis  in- 


LEAD.  675 

duced  by  the  poison.  The  sudden  cases  of  blindness  are  probably  due 
to  uraemia,  and  the  prognosis  in  all  forms  depends  on  the  duration  of 
the  neuritis,  and,  in  the  case  of  albuminuria,  on  the  extent  to  which  the 
kidney  is  involved.  In  early  cases  of  neuritis,  the  disease  can  gener- 
ally be  arrested  and  even  complete  restitution  may  take  place,  but  if  it 
be  neglected,  optic  atrophy  follows. 

Under  saturnine  Encephalopathia,  a  number  of  disorders  of  the  brain 
are  classed  together.  They  are  comparatively  rare  at  the  present  time, 
and  their  onset  generally  indicates  long  standing  and  neglected  lead 
intoxication,  although  in  some  cases  the  patient  has  been  shown  to  be 
exposed  to  the  poison  for  only  a  short  period.  An  attempt  has  been 
made  to  divide  the  symptoms  of  encephalopathia  saturnina  into  four 
groups,  but  as  the  author  himself  remarks,  one  of  the  most  character- 
istic features  is  the  rapidity  with  which  the  disease  changes  from  one 
type  to  another,  and  the  diversity  of  the  symptoms  present  at  one 
time.  These  cerebral  symptoms  sometimes  appear  suddenly,  while  in 
other  cases  they  are  heralded  by  violent  headache,  giddiness  and  sleep- 
lessness, or  by  amblyopia,  deafness,  great  depression,  stupor,  weakness, 
and  tremor.  Later,  sudden  mania  and  delirium,  with  convulsions  re- 
sembling chorea  or  epilepsy,  hallucinations  and  illusions  indistinguish- 
able from  those  of  alcoholic  delirium,  sudden  apoplectic  paralysis, 
ataxia,  partial  analgesia,  hypersesthesia,  or  coma  may  occur  separately 
or  in  succession.  Oliver  states  that  the  encephalopathic  symptoms  are 
especially  liable  to  occur  in  persons  addicted  to  alcohol. 

In  animals  cerebral  symptoms  are  readily  induced  by  lead,  either 
by  intravenous  injection  (Harnack),  or  by  chronic  poisoning  with  the 
ordinary  salts.  Chorea,  tremors  and  general  convulsions  have  been 
caused  in  this  way  in  dogs. 

The  encephalopathia  is  obviously  of  cerebral  origin  for  the  most 
part,  although  the  lower  divisions  of  the  central  nervous  system  are 
also  involved  in  many  cases.  In  several  autopsies  of  patients  dying 
from  lead  poisoning,  atrophy  of  parts  of  the  cerebrum,  or  haemorrhages 
have  been  found,  and  very  frequently  disease  of  the  brain  vessels  — 
periarteritis,  endoarteritis,  atheroma  or  hyaline  degeneration  —  has 
been  met  with.  In  other  cases  of  undoubted  encephalopathia  in  man, 
no  such  lesions  have  been  observed,  and  in  animals  poisoned  by  Har- 
nack's  method  they  are  certainly  not  present.  Many  of  the  symptoms 
are  obviously  not  due  to  these  gross  lesions,  for  the  suddenness  of  their 
onset  and  of  the  recovery  precludes  any  such  explanation,  and  show 
that  lead  has  also  a  direct  action  on  the  brain  cells.  Lugaro  and 
Schaffer  have  described  some  alterations  in  the  chromatin  and  the 
dendrites  of  the  nerve  cells,  which  they  suppose  indicate  this  direct 
affection ;  McCarthy  found  marked  changes  in  the  capillaries  of  the 
cerebral  cortex  in  a  dog  which  was  subjected  to  the  action  of  lead  for 
two  months  and  which  presented  symptoms  of  cerebral  disorder  similar 
to  those  met  with  in  chronic  poisoning  in  man. 

It  must  be  noted  that  in  addition  to  these  generally  recognized  symp- 
toms of  encephalopathia  saturnina,  several  obscure  chronic  nervous 


676  THE  HEAVY  METALS. 

diseases  have  been  ascribed  by  Putnam  and  others  to  lead  intoxication, 
and  it  is  certainly  possible  that  its  action  may  prove  to  be  even  more 
wide-reaching  and  insidious  than  is  generally  recognized  at  present,  but 
it  does  not  seem  profitable  to  enter  upon  further  details  in  the  present 
state  of  the  subject. 

Another  organ  acted  on  by  lead,  especially  in  prolonged  poisoning, 
is  the  Kidney,  which  is  often  found  to  present  a  typical  red  granular 
nephritis.  During  life  the  urine  presents  the  ordinary  appearances  of 
this  disease,  being  copious  in  amount  and  of  low  specific  gravity,  and 
containing  comparatively  small  quantities  of  albumin  or  casts.  In 
some  cases  in  man,  the  kidney  has  presented  a  mixture  of  parenchyma- 
tous  and  interstitial  disease,  while  in  animals  the  parenchyma  alone  is 
affected,  perhaps  because  the  experiments  have  not  lasted  long  enough. 
The  disease  of  the  kidney  from  lead  poisoning,  as  from  other  sources, 
may  cause  dropsy,  uraemia  and  amblyopia,  but  it  is  to  be  noted  that 
the  brain  and  eye  may  be  affected  in  cases  in  which  there  is  no 
nephritis. 

Gout  is  very  common  in  lead  poisoning,  which  evidently  predisposes 
to  this  disease,  if  it  does  not  actually  cause  it,  for  Garrod  states  that  in 
one-fourth  of  the  cases  of  gout  treated  by  him  there  was  a  history  of 
lead  poisoning.  It  occurs  only  after  prolonged  exposure  to  the  metal, 
and  differs  from  ordinary  gout  in  the  rapidity  with  which  it  spreads 
from  one  joint  to  another,  as  well  as  in  some  other  features  (Luethje). 
Thus  gout  is  seen  without  nephritis  and  vice  versa,  the  two  affections 
being  quite  independent  of  each  other.  The  uric  acid  of  the  urine  is 
not  increased,  while  that  of  the  blood  is  said  to  be  abnormally  high. 
In  districts  where  ordinary  gout  is  rare,  lead  poisoning  seldom  leads 
to  it,  but  where  ordinary  gout  is  met  with,  it  is  a  fairly  common  com- 
plication of  saturninism. 

Another  condition  in  which  lead  poisoning  may  act  as  a  predisposing 
factor  is  Arteriosclerosis ;  the  malnutrition,  anaemia,  and  renal  changes 
induced  by  the  metal  would  in  themselves  tend  to  induce  changes  in 
the  vessels  throughout  the  body,  and  degeneration  of  their  walls  is  met 
with  in  a  considerable  proportion  of  cases  of  very  prolonged  exposure 
to  it. 

Lead  poisoning  runs  no  definite  course.  As  a  general  rule  the 
anaemia,  wasting,  constipation  and  weakness  appear  early,  and  then 
colic  may  follow,  or  paralysis,  or  arthralgia.  Nephritis,  encephalopa- 
thia,  anesthesia  and  gout  are  rarer,  and  as  a  rule  only  occur  in  very 
prolonged  poisoning.  Any  one  of  these  symptoms  may  be  present 
alone,  and  the  diagnosis  is  then  very  difficult.  In  doubtful  cases  the 
urine  ought  to  be  examined  after  the  administration  of  iodide,  or  the 
stools  may  be  tested  for  lead.  Every  case  in  which  lead  is  found  in 
the  urine  is  not  necessarily  one  of  lead  intoxication,  however,  for  it 
has  been  detected  in  a  number  of  perfectly  healthy  individuals. 

It  is  impossible  at  present  to  give  any  general  explanation  for  the 
diversity  of  the  forms  of  chronic  lead  poisoning.  The  central  nervous 
system  is  certainly  acted  on,  both  in  its  higher  and  lower  divisions, 


LEAD.  677 

but  it  is  still  disputed  how  far  the  paralysis,  arthralgia  and  anaesthesia 
are  symptoms  of  central  action,  and  how  far  they  are  due  to  peripheral 
neuritis.  All  of  the  symptoms,  however,  except  those  from  the  mouth, 
stomach  and  kidney,  and  the  anaemia  and  gout  seem  to  be  due  to  affec- 
tions of  either  the  central  or  peripheral  nervous  system.  The  lead 
line,  metallic  taste  and  nausea,  and  perhaps  the  constipation,  would 
seem  to  be  connected  with  the  excretion  of  the  metal  along  the  ali- 
mentary canal,  while  the  renal  action  is  probably  of  the  same  nature 
as  that  inducing  periarteritis  in  the  brain  and,  as  is  alleged,  in  the 
lungs  under  some  conditions.  The  anaemia  indicates  an  action  on  the 
red  cells  of  the  blood,  and  the  gout  some  disturbance  of  the  general 
nutrition.  Attempts  have  been  made  to  elucidate  the  nature  of  this 
action  om  metabolism  by  estimating  the  urea  and  other  constituents  of 
the  urine,  but  no  important  light  has  been  thrown  on  it  by  this  means, 
nor  in  fact  are  significant  results  to  be  hoped  for  in  a  disease  which 
offers  so  many  and  so  diverse  types  as  lead  poisoning. 

Lead  acts  upon  so  many  tissues  that  it  might  be  expected  to  have 
some  distinctive  action  upon  the  simpler  organisms,  but,  as  a  matter  of 
fact,  it  seems  less  poisonous  to  them  than  most  other  heavy  metals. 

PREPARATIONS. 

PLUMBI  ACETAS  (U.  S.  P.,  B.  P.),  lead  acetate,  sugar  of  lead  (Pb(C2H3O2)2 
-f  3H2O),  forms  colorless  crystals,  with  a  sweetish,  astringent,  afterwards 
metallic  taste,  very  soluble  in  water,  less  so  in  alcohol.  0.05-0.3  G.  (1-5 
grs.). 

Unguentum  Plumbi  Acetatis  (B.  P.),  4  per  cent. 

Suppositoria  Plumbi  Composita  (B.  P.)  ;  each  contains  3  grs.  of  lead  acetate 
and  1  gr.  of  opium. 

Pilula  Plumbi  cum  Opio  (B.  P.)  contains  about  12J  per  cent,  of  opium. 
2-4  grs. 

Liquor  Plumbi  Subacetatis  (U.  S.  P.),  Liquor  Plumbi  Subacetatis  Fortis  (B.  P.), 
Goulard's  extract,  an  aqueous  solution  containing  about  25  per  cent,  of  lead 
subacetate  (approximately  Pb(C2H3O2)2PbO).  When  exposed  to  the  air,  the 
insoluble  lead  carbonate  is  formed.  The  subacetate  solutions  are  alkaline  in 
reaction. 

Liquor  Plumbi  Subacetatis  Dilutus  (U.  S.  P.,  B.  P.),  lead  water,  Goulard's 
lotion  or  water,  a  solution  containing  about  7.5  parts  (3  parts  B.  P.)  of  the 
subacetate  in  1,000  parts  of  water. 

Glycerinum  Plumbi  Subacetatis  (B.  P.). 

Unguentum  Glycerini  Plumbi  Subacetatis  (B.  P.). 
--Ceratum  Plumbi  Acetatis  (U.  S.  P.),  Goulard's  cerate. 

Plumbi  Carbonas  (B.  P.),  white  lead  ((PbCO3)2Pb(OH)2). 

Unguentum  Plumbi  Carbonatis  (B.  P.). 

Plumbi  lodidum  (U.  S.  P.,  B.  P.)  (PbI2). 

Emplastrum  Plumbi  lodidi  (B.  P. ). 

Unguentum  Plumbi  lodidi  (B.  P.). 

Plumbi  Oxidum  (U.  S.  P.,  B.  P.),  litharge  (PbO). 

Plumbi  JS/itras  (U.  S.  P.)  (Pb(NO3)2). 

Lead  plaster  or  diachylon  plaster,  Emplastrum  Plumbi,  is  formed  from  the 
oxide  but  is  mentioned  elsewhere.  (See  Part  VI.) 

Therapeutic  Uses.  —  Lead  is  used  in  therapeutics  only  for  its  astrin- 
gent action.  The  acetate  is  prescribed  internally  in  diarrhoea,  gener- 


678  THE  HEAVY  METALS. 

ally  along  with  opium,  and  always  in  pill  form,  as  the  solution  would 
act  on  the  stomach  and  have  less  effect  on  the  bowel.  It  has  been 
tried  in  dysentery  and  cholera,  but  has  proved  of  little  value.  Lead 
has  also  been  advised  in  cases  of  haemorrhage  from  the  lungs,  kidneys 
and  uterus,  but  is  quite  valueless  here,  as  it  acts  as  a  styptic  only  when 
applied  locally.  Still  less  reason  is  there  for  its  use  in  nephritis,  cys- 
titis and  similar  conditions. 

Externally,  a*  solution  of  the  acetate  or  the  dilute  solution  of  the 
subacetate  is  used  as  an  astringent  lotion  in  burns  and  as  an  injection 
in  gonorrhoea.  White  lead  has  been  advised  as  a  dusting  powder  in 
burns  and  skin  affections,  but  is  not  superior  in  any  way  to  other 
similar  preparations,  and  is  liable  to  be  absorbed.  Nitrate  of  lead  has 
a  reputation  in  the  treatment  of  onychia. 

Lead  ought  not  to  be  employed  externally  or  internally  except  for 
a  short  time  as  otherwise  symptoms  of  poisoning  may  arise. 

Poisoning.  —  In  acute  lead  poisoning,  the  indications  are  its  removal 
from  the  stomach  by  washing,  and  its  precipitation,  which  may  be 
best  accomplished  by  solutions  of  the  sulphates  such  as  of  magnesium 
sulphate.  In  the  absence  of  the  sulphates,  white  of  egg  or  milk  is 
given  to  form  the  insoluble  albuminate. 

In  chronic  poisoning,  the  general  treatment  is  the  removal  of  the 
patient  from  the  danger  of  further  poisoning,  the  administration  of 
iodide  of  potassium,  and  nutritious,  strengthening  diet.  The  iodide  of 
potassium  has  been  said  to  accelerate  the  elimination  of  lead  by  the 
kidneys,  but  according  to  Lehmann's  experiments  is  not  superior  to 
the  bromide  or  the  chloride  of  potassium,  and  it  has  been  recently  denied 
that  it  has  any  effect  on  the  excretion  by  the  urine  or  by  the  intestine, 
by  which  most  of  the  lead  escapes  from  the  body.  In  practice,  how- 
ever, the  iodide  is  always  used.  Diuretics  may  be  prescribed,  and 
hot  baths ;  sulphur  baths  are  especially  recommended,  and  massage  is 
said  to  hasten  the  elimination  of  the  poison. 

In  colic,  morphine  or  opium  is  often  necessary  to  allay  the  pain. 
Belladonna  or  atropine  is  used  less  frequently,  and  nitrite  of  amyl  is 
said  to  be  efficient  for  a  short  time.  In  the  intervals  between  the 
paroxysms,  a  saline  cathartic  is  often  necessary  to  relieve  the  constipa- 
tion, or  if  the  vomiting  prevents  this,  a  large  enema  may  be  thrown 
into  the  bowel. 

In  arthralgia,  the  pain  may  necessitate  the  giving  of  opiates.  In 
anaesthesia  and  encephalopathia,  the  treatment  is  expectant  and  symp- 
tomatic ;  for  instance,  in  mania,  or  violent  delirium,  chloral  may  be 
necessary. 

In  paralysis,  strychnine  may  be  used  along  with  the  general  treat- 
ment, but  the  chief  reliance  is  to  be  placed  on  the  electrical  stimula- 
tion of  the  paralyzed  muscles,  first  with  the  galvanic  current,  and,  as 
recovery  sets  in,  with  the  induction  coil.  Massage  of  the  muscles  is 
also  of  benefit. 

Nephritis  and  gout  due  to  lead  poisoning  are  to  be  treated  in  the 
same  way  as  those  arising  from  other  causes. 


LEAD.  679 

In  lead  works  and  paint  factories,  much  may  be  done  to  prevent  lead 
poisoning.  Dust  is  to  be  avoided  as  much  as  possible,  and  where  this 
is  necessarily  present,  the  rooms  ought  to  be  thoroughly  ventilated. 
The  necessity  of  frequent  bathing  and  of  thorough  washing  before 
meals  ought  to  be  impressed  on  the  workmen,  and  no  food  is  to  be 
admitted  to  the  works.  A  lemonade  made  with  sulphuric  acid  is  often 
recommended  as  a  prophylactic  measure  with  the  object  of  changing 
the  lead  to  the  insoluble  sulphate  and  thus  rendering  it  less  readily 
absorbed.  Poisoning  may,  however,  be  induced  by  lead  sulphate, 
though  less  often  than  by  the  carbonate,  which  is  dissolved  by  water 
in  the  presence  of  free  carbonic  acid,  and  which  is  changed  to  the 
slightly  soluble  chloride  in  the  stomach. 

When  symptoms  of  poisoning  have  appeared,  the  patient  ought  not 
to  be  allowed  to  work  again,  or  at  least  only  after  a  long  interval. 
Weak  and  anaemic  men  ought  not  to  be  admitted  as  workmen,  and 
women  are  not  to  be  employed  in  lead  works  more  than  can  be 
avoided. 

BIBLIOGRAPHY. 

Harnack.       Arch.  f.  exp.  Path.  u.  Pharm.,  ix.,  p.  152. 

Wyss.     Virchow's  Arch.,  xcii.,  p.  193. 

Maier.     Ibid.,  xc.,  p.  455. 

Annuschat.     Arch.  f.  exp.  Path.  u.  Pharm.,  vii.,  p.  45  ;  x.,  p.  261. 

Lehmann.     Zts.  f.  physiolog.  Chem.,  vi.,  p.  528. 

Mann.       Brit.  Med.  Jour.,  1893,  i.,  p.  401. 

Miura.     Berl.  klin.  Woch.,  1890,  p.  1005. 

Oddo  et  Silbert.     Kev.  de  Med.,  1892,  p.  295. 

Gaucher.     Ibid.,  1881,  p.  877. 

Riegel.     Deutsch.  Arch.  f.  klin.  Med.,  xxi.,  p.  175. 

Borgen.     Ibid.,  Ivi.,  p.  248. 

Ellenberger  u.  Hofmeister.     Arch.  f.  Thierheilkunde,  x.,  p.  216. 

Westphal,     Archiv  f.  Psychiatric,  xix.,  p.  620. 

Stieglitz.     Ibid.,  xxiv.,  p.  1. 

Ceni.     Ibid.,  xxix.,  p.  566. 

Luethje.     Ztschr.  f.  klin.  Med.,  xxix.,  p.  266  ;  xxxi.,  p.  112. 

Stood.     Arch.  f.  Ophthalmol.,  xxx.,  iii.,  p.  215. 

Kchroeder.    Ibid.,  xxxi.,  i.,  p.  229. 

Cornil  et  Brault.     Journ.  de  I'Anat.,  1883,  p.  205. 

Coen  e  D' Ajutolo.     Ziegler's  Beitrage,  iii.,  p.  451. 

Charcot.     Arch,  de  Physiol.,  1881,  p.  126. 

Walton.     Boston  Med.  and  Surg.  Jour.,  cxxiii.,  p.  411. 

Webber.     Ibid. ,  cxxv. ,  p.  462. 

Putnam.     Ibid.,  cxvii.,  pp.  73,  596 ;  cxxviii.,  p.  187. 

Ebstein.     Virchow's  Arch.,  cxxxiv.,  p.  541. 

Eichhorst.     Ibid.,  cxx.,  p.  217. 

Lugaro.     Centralbl.  f.  Physiol.,  1897,  p.  211. 

Scha/er.     Ung.  Archiv  f.  Med.,  ii.,  p.  43. 

Provost  et  Binet.     Kev.  Med.  de  la  Suisse  Komande,  1889. 

Lorimer.     Brit.  Med.  Jour.,  1886,  ii.,  p.  163. 

Oliver.     Lancet,  1891,  ii.,  p.  530.     Lead  poisoning,  London,  1891. 

Virchow.     Berl.  klin.  Woch.,  1884,  p.  75. 

Trimborn.     Centralbl.  f.  klin.  Med.,  1891,  p.  44. 

White  and  Pepper.     Trans,  of  Amer.  Assoc.  of  Physicians,  1901,  p.  410. 

McCarthy.     Univ.  of  Pennsylvania  Med.  Bull.,  January,  1902. 

Billings.     Journ.  Amer.  Med.  Ass.,  1904,  p.  772. 


680  THE  HEAVY  METALS. 

V.     COPPER. 

Copper  seldom  gives  rise  to  poisoning,  and  is  much  less  frequently 
used  in  medicine  than  many  of  the  other  heavy  metals.  The  soluble 
salts  precipitate  proteids  from  solution,  and  are  therefore  astringent 
when  applied  to  the  mucous  membranes  and  to  wounded  surfaces.  In 
larger  quantities  they  are  somewhat  irritant  and  corrosive,  although 
much  less  so  than  mercury. 

Symptoms.  —  The  copper  salts  have  a  harsh,  metallic,  astringent 
taste,  and  when  swallowed  in  some  quantity  cause  nausea,  salivation 
and  vomiting.  The  most  of  the  salt  is  thus  removed,  and  no  further 
symptoms  are  observed.  Large  quantities,  however,  induce  corrosion 
of  the  walls  of  the  stomach  and  intestine,  and  give  rise  lo  violent  vom- 
iting and  purging,  the  copper  giving  a  blue  or  green  color  to  the  vom- 
ited matter  and  the  stools,  and  blood  appearing  in  them  later  from  the 
corrosion  of  the  mucous  membrane.  Violent  pain  in  the  abdomen  is 
complained  of,  and  the  usual  symptoms  of  acute  corrosive  poisoning 
may  follow  —  collapse,  with  weak  pulse  and  respiration,  headache, 
giddiness,  unconsciousness,  delirium,  coma,  convulsions  and  paralysis. 
These  may  prove  fatal  in  a  few  hours,  but  more  frequently  the  patient 
lives  for  several  days  to  eventually  sink  from  exhaustion. 

The  nausea,  vomiting  and  purging  of  acute  copper  poisoning  are  due  to  the 
local  effect  on  the  mucous  membranes  of  the  stomach  and  intestine.  In  fact, 
although  some  copper  is  absorbed  in  these  cases,  there  is  no  reason  to  sup- 
pose that  any  of  the  acute  symptoms  are  due  to  it,  for  they  are  all  induced 
by  other  poisons  which  act  only  as  gastro-intestinal  irritants. 

It  is  still  disputed  whether  chronic  copper  poisoning  occurs  in  man.  The 
question  is  of  great  hygienic  interest,  because  copper  is  used  very  often  to 
give  color  to  preserved  vegetables,  such  as  peas,  is  added  to  flour  to  improve 
the  bread,  and  may  enter  into  the  food  from  the  use  of  copper  cooking  ves- 
sels, and  in  a  variety  of  other  ways.  In  copper  and  brass  workers,  gastro- 
intestinal catarrh,  or  colic  and  diarrhoea,  occur  occasionally  and  are  ascribed 
to  the  copper  swallowed  in  the  course  of  their  occupation.  The  dust  inhaled 
may  similarly  cause  laryngeal  irritation  and  bronchitis.  The  skin  and  hair 
have  often  a  greenish  tint,  and  a  green  line  on  the  teeth,  just  where  they 
enter  the  gums,  is  known  as  the  copper  line  ;  but  it  is  believed  that  these  are 
due  largely  to  the  copper  dust  deposited  on  the  skin,  hair  and  teeth,  and  not 
to  the  excretion  of  the  metal.  Local  paralysis,  anaemia,  tremor,  emaciation 
and  cutaneous  eruptions  are  said  to  have  followed  these  symptoms  in  some 
cases,  and  have  been  held  to  indicate  that  copper  is  poisonous  after  absorp- 
tion, but  it  may  fairly  be  doubted  whether  these  symptoms  are  really  due  to 
the  copper  or  to  the  lead,  arsenic  and  other  poisons  often  associated  with  it. 
It  is  certain  that  only  a  very  small  proportion  of  workers  suffer  from  any 
symptoms  whatever,  and  that  the  great  majority  enjoy  excellent  health. 
Furthermore,  copper  has  been  taken  in  the  form  of  the  metal,  or  of  its  soluble 
salts  for  prolonged  periods  without  any  symptoms  being  elicited  except  those 
of  slight  intestinal  catarrh  and  some  nausea.  Animals  have  been  fed  with 
food  containing  large  doses  of  copper  for  many  months,  apparently  without 
any  symptoms  of  poisoning,  and  copper  is  found  so  regularly  in  the  tissues 
of  man  and  animals  that  it  may  be  regarded  as  a  normal  constituent,  although 
its  function  is  altogether  unknown  and  it  may  be  merely  stored  up  on  its  way 
to  excretion.  Of  course  it  is  possible  that  there  exists  in  certain  persons  an 
idiosyncrasy  for  copper,  and  that  these  suffer  from  the  ingestion  of  quantities 
which  are  harmless  in  others.  But  until  the  symptoms  have  been  more  def- 


COPPER.  681 

initely  determined,  and  have  been  shown  not  to  arise  from  the  other  poisons 
associated  with  copper,  it  is  impossible  to  consider  this  form  of  intoxication 
as  satisfactorily  established,  and  there  is  no  reason  to  suppose  that  poisoning 
can  be  induced  by  small  quantities  of  copper  such  as  are  contained  in  pre- 
served vegetables  or  in  food  cooked  in  copper  vessels. 

In  animals  the  general  action  may  be  elicited  by  the  injection  of  copper 
into  the  blood  or  subcutaneously.  The  ordinary  salts  are  inadmissible  by 
the  former  method,  as  they  precipitate  the  proteids  of  the  blood  and  cause 
embolism,  and  double  salts,  such  as  the  tartrate  of  copper  and  sodium,  or 
proteid  compounds,  such  as  the  albuminate  dissolved  by  means  of  alkalies, 
have  therefore  been  used.  A  special  form  of  proteid  combination  has  been 
formed  in  the  same  way  as  artificial  ferratin,  and  is  found  to  act  more  slowly 
than  ordinary  salts.  In  the  frog,  copper  induces  great  weakness  and  event- 
ually complete  paralysis  of  the  spontaneous  movements  and  of  the  heart. 
Harnack  attributed  this  to  direct  action  on  the  muscle,  but  later  observers 
have  found  that  the  central  nervous  system  is  primarily  affected,  and  that  the 
muscles  retain  their  irritability  after  complete  paralysis  of  the  spinal  cord. 
There  is,  however,  a  direct  action  on  the  muscles  also,  for  they  lose  their 
irritability  very  soon  after  death,  and  even  before  the  spontaneous  move- 
ments have  ceased,  the  contraction  of  the  muscles  on  direct  stimulation  being 
much  weaker  than  usual.  Very  often  fibrillary  contractions  are  observed 
early  in  the  frog,  but  it  is  unknown  whether  these  are  of  central  or  of  peri- 
pheral origin.  The  heart  is  somewhat  accelerated  at  first  by  very  small 
quantities,  but  later  becomes  slow  and  weak,  and  finally  ceases  in  diastole 
before  the  skeletal  muscles  are  paralyzed  ;  the  changes  in  the  heart  are  due 
to  direct  action  on  the  muscle. 

In  mammals  the  intravenous  injection  of  copper  does  not  cause  vomiting, 
according  to  most  authors,  thus  proving  that  the  emetic  action  is  due  to  the 
irritation  of  the  stomach,  and  not  to  any  action  on  the  medulla.  When 
large  quantities  are  injected,  the  locomotion  soon  becomes  slow,  clumsy  and 
weak,  and  later,  complete  paralysis  of  the  spontaneous  movements  follows. 
The  heart  and  respiration  seem  equally  involved,  but  the  respiration  ceases 
somewhat  earlier  than  the  heart.  The  blood-pressure  rises  slightly  after  the 
intravenous  injection  of  copper,  but  afterwards  falls,  partly  on  account  of 
the  weakness  of  the  heart,  and  partly  from  failure  of  the  vaso-motor  nerves 
to  maintain  the  contraction  of  the  blood  vessels.  When  an  animal  survives 
longer,  violent,  sometimes  bloody,  diarrhosa  is  generally  induced  by  copper, 
as  by  most  of  the  other  heavy  metals.  The  animals  lose  flesh  rapidly,  and 
refuse  food,  and  the  urine  often  contains  albumin,  and  according  to  some 
authors,  haemoglobin  and  blood.  In  the  rabbit  some  icterus  and  anaemia  is 
said  to  occur  from  the  destruction  of  the  red  blood  cells,  and  fatty  degen- 
eration of  the  liver,  kidney,  and  heart  have  been  observed.  Others  have 
found  ecchymoses  and  congestion  along  the  intestine  and  in  the  kidney  to 
be  the  chief  lesions.  Similar  results  are  obtained  in  rabbits  when  copper  is 
given  by  the  mouth,  as  this  animal  is  incapable  of  rejecting  the  poison  by 
vomiting.  In  the  dog,  on  the  other  hand,  poisonous  doses  seem  to  be  re- 
moved by  vomiting  when  they  are  given  by  the  mouth  ;  it  is  possible,  how- 
ever, that  animals  may  show  symptoms  of  poisoning  from  the  prolonged  ad- 
ministration by  the  mouth  of  quantities  just  too  small  to  cause  vomiting. 

Copper  is  certainly  absorbed  from  the  stomach  and  intestine,  for 
large  quantities  have  been  found  in  animals  fed  on  it  for  some  time. 
Baum  and  Seeliger  state  that  a  very  large  proportion  of  the  poison  is 
absorbed  when  small  doses  are  given,  but  the  proportion  lessens  as  the 
dose  is  increased.  It  also  passes  into  the  blood  from  other  mucous 
surfaces  and  from  wounds.  It  is  said  to  have  a  strong  affinity  for 
haemoglobin,  and  to  form  with  it  a  compound  which  Kobert  has  named 


682  THE  HEAVY  METALS. 

cuprohsemol,  and  which  is  stated  to  be  formed  very  rapidly  when 
copper  is  injected  into  the  blood,  the  metal  leaving  the  serum  and 
attaching  itself  to  the  corpuscles  at  once.  The  copper  absorbed  from 
the  intestine  and  stomach  is  lodged  chiefly  in  the  liver,  less  in  the 
spleen,  kidney  and  thyroid.  It  is  excreted  in  the  bile,  urine  and  sa- 
liva, in  the  intestinal  secretions,  and  in  traces  in  the  milk,  and  is  said 
to  pass  from  the  mother  to  the  fetus  in  utero.  Copper  is  found  in 
small  quantities  in  these  organs  and  secretions  in  man  and  in  animals 
that  have  not  been  treated  with  it,  but  in  much  larger  amount  after 
prolonged  administration.  Taken  by  the  mouth,  it  fails  to  cause  gen- 
eral poisoning,  because  it  is  slowly  absorbed,  and  also  because  what  is 
absorbed  is  withdrawn  from  the  blood  by  the  liver. 

Copper  is  found  as  a  normal  constituent  of  the  blood  in  many  of  the  in- 
vertebrates, in  which  it  performs  the  same  function  as  the  iron  of  the  haemo- 
globin in  the  vertebrates.  It  has  been  detected  in  one  of  the  pigments  of 
birds'  feathers,  and,  as  has  been  stated,  is  so  frequently  found  in  the  tissues 
of  mammals,  both  wild  and  domesticated,  that  it  may  be  regarded  as  a  nor- 
mal constituent.  Oysters  and  other  animals  take  it  up  in  large  quantities 
when  they  live  in  water  rich  in  copper,  and  apparently  are  not  injured  by  it. 
Many  of  the  higher  plants,  notably  the  grape  vine,  are  said  to  be  remark- 
ably improved  by  the  sprinkling  of  copper  on  their  leaves,  and  this  is  not 
only  from  the  destruction  of  parasites,  for  vines  free  from  any  disease  show 
a  more  luxuriant  foliage,  and  bear  more  and  larger  fruit  than  other  healthy 
plants,  which  are  not  treated  with  it.  On  the  other  hand,  copper  is  a  deadly 
poison  to  several  of  the  lower  plants.  Thus  traces  of  copper  added  to  the 
water  in  which  they  live,  destroy  some  of  the  simpler  algse,  and  Naegeli 
asserts  that  one  part  of  copper  in  one  thousand  million  parts  of  water  is 
sufficient  to  kill  these  plants.  The  parasites  of  the  grape  vine,  potato,  apple, 
and  other  plants  are  destroyed  by  spraying  the  plants  with  copper,  and 
yeast  ceases  growing  in  a  0.02  per  cent,  solution,  while  penicillium  seems  to 
be  almost  immune  to  its  action.  Locke  found  that  the  traces  of  copper 
contained  in  water  distilled  in  copper  vessels  was  sufficient  to  destroy 
tubifex  (one  of  the  annelid  worms)  and  tadpoles,  while  Bucholtz  states  that 
the  development  of  bacteria  is  stopped  by  a  solution  of  copper  sulphate 
under  one  per  cent,  in  strength.  Copper  thus  seems  to  have  a  very  power- 
ful poisonous  action  on  certain  living  forms  and  to  be  harmless  to  others, 
and  the  subject  deserves  further  investigation.  It  is  possible  that  it  may 
prove  to  act  prejudicially  to  some  human  parasites,  and  it  is  certainly  less 
dangerous  to  man  than  many  other  remedies  used  as  parasiticides  and  disin- 
fectants. 

PREPARATIONS. 

Cupri  Sulphas  (U.  S.  P.,  B.  P.)  (CuSO4  +  5H2O),  large,  transparent,  deep 
blue  crystals,  without  odor,  but  with  a  nauseous,  metallic  taste,  soluble  in 
water,  scarcely  so  in  alcohol.  Dose,  as  an  astringent,  0.015-0.1  G.  (J-2  grs.); 
as  an  emetic,  0.3-0.6  G.  (5-10  grs.). 

Therapeutic  Uses. — Copper  sulphate  is  used  internally  only  as  an 
emetic,  and  for  this  purpose  ought  to  be  given  in  about  one  per  cent, 
solution.  It  acts  promptly,  and  does  not  leave  so  much  depression 
and  nausea  as  other  metallic  emetics,  and  for  this  reason  is  unsuitable 
as  an  expectorant.  In  phosphorus  poisoning  it  is  especially  valua- 
ble, as  in  addition  to  causing  evacuation  of  the  stomach,  the  metal  is 
deposited  on  the  particles  of  phosphorus  and  prevents  their  absorption. 

Externally  copper  sulphate  is  used  as  an  astringent  injection  in 


ZINC.  683 

gonorrhoea,  and  occasionally  as  a  lotion  in  ulcers  and  wounds;  for  this 
purpose  it  is  employed  in  one  per  cent,  solution.  The  solid  crystals 
are  sometimes  used  to  touch  exuberant  granulations  for  their  astrin- 
gent and  corrosive  effect. 

Small  quantities  of  copper  sulphate  have  recently  been  used  to  destroy 
the  algse  which  grow  in  reservoirs  and  often  give  the  water  a  disagree- 
able odor  and  taste.  The  proportion  of  copper  required  for  this  pur- 
pose is  about  one  part  in  a  million  or  sometimes  in  fifty  millions ; 
this  treatment  does  not  render  the  water  deleterious  to  man,  for  much 
larger  quantities  of  copper  have  been  taken  constantly  without  injury. 
The  suggestion  has  also  been  made  to  disinfect  water  contaminated 
with  typhoid  bacilli,  and  some  success  has  been  recorded ;  the  propor- 
tion of  copper  required  for  this  purpose  appears  to  be  greater  than  that 
necessary  to  destroy  the  less  resistant  algse. 

The  chloride  of  copper  is  a  much  more  irritant  and  antiseptic  substance 
than  the  sulphate.  The  albuminate  of  copper,  cupratin,  which  is  formed 
from  the  albuminate  by  heating  with  alkalies,  and  cuprohsemol,  a  combina- 
tion of  copper  and  haemoglobin,  have  been  suggested  recently  as  non-irritant 
preparations  suitable  for  internal  use,  but  no  condition  is  known  at  present 
in  which  the  general  action  of  copper  is  of  benefit. 

In  cases  of  Poisoning  with  copper  salts,  the  stomach  generally  rejects  the 
metal  by  vomiting,  and  no  emetic  is  required.  Non-corrosive  compounds 
may  be  formed  by  giving  milk,  egg,  or  other  forms  of  albumin,  tannic  acid, 
magnesia,  or  ferrocyanide  of  potassium.  Morphine  may  be  required  for  the 
pain,  ice  to  stop  the  vomiting. 

BIBLIOGRAPHY. 

HarnacL     Arch.  f.  exp.  Path.  u.  Pharm.,  iii.,  p.  44;  xvii.,  p.  145. 

Klemptner.     Ibid.,  1895,  i.,  p.  346. 

Lehmann.     Arch.  f.  Hygiene,  xxiv.,  p.  1  ;  xxvii.,  p.-l  ;  xxxi.,  p.  279. 

Tschirch.  Das  Kupfer,  vom  Standpunkte  der  gericht.  Chemie,  Toxikologie  u.  Hy- 
giene, Stuttgart,  1893. 

Schwartz.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxv.,  p.  437. 

Robert.     Deutsch.  med.  Woch.,  1895,  p.  5. 

De  Moor.     Arch,  de  Pharmacodynamique,  i.,  p.  81. 

Baum  u.  Seeliger.  Centralbl.  f.  Physiol.,  1896,  pp.  714,  752 ;  1897,  p.  797  ;  1898, 
p.  108. 

Trolldenier.     Ibid.,  1898,  p.  108. 

Locke.     Journ.  of  Phys.,  xviii.,  p.  319. 

Ringer.     Ibid.,  xxii.,  p.  xiv. 

Wolf.     Ztschr.  f.  physiolog.  Chem.,  xxvi.,  p.  442. 

Murray.     British  Med.  Journ.,  1900,  i.,  p.  1334. 

Lewin.     Deutsch.  med.  Woch.,  1900,  p.  689. 

Kurth.     Medical  Record,  1900,  Nov.  10th. 

Richter.     Centralbl.  f.  Bacteriologie  (ii.),  vii.,  p.  417. 

Moore,  Kraemer.     Amer.  Journ.  of  Pharmacy,  1904,  pp.  553,  574. 

VI.     ZINC. 

The  effects  of  zinc  resemble  those  of  copper  so  closely  that  they  need 
only  brief  mention.  Like  copper,  the  soluble  salts  form  insoluble  albu- 
minates  and  therefore  possess  an  astringent  action,  or  in  large  quantities 
act  as  irritants  and  corrosives.  The  sulphate  is  the  soluble  salt  most 
commonly  used  in  medicine,  but  the  chloride  has  frequently  given  rise 


684  THE  HEAVY  METALS. 

to  corrosive  poisoning,  and  is  therefore  of  greater  importance  than 
the  chloride  of  copper.  The  sulphate  is  much  less  irritant  and  more 
astringent  than  the  chloride,  which  is  used  only  as  a  caustic  and  dis- 
infectant. 

Symptoms.  —  The  sulphate  of  zinc  has  a  harsh,  metallic  taste,  and  in 
small  doses  causes  nausea  and  vomiting,  'in  larger  quantities  violent 
vomiting  and  purging,  pain  in  the  abdomen  and  collapse ;  these 
symptoms  are  due  to  the  local  action  on  the  stomach  and  intestine. 
The  insoluble  zinc  oxide  and  carbonate  are  less  liable  to  cause  acute 
irritation  than  the  sulphate,  but  their  prolonged  ingestion  has  given 
rise  to  dyspepsia  and  constipation  or  diarrhoea  in  some  cases.  The 
continued  administration  of  zinc  salts  has  no  effects  in  man,  except 
those  of  disordered  digestion  and  constipation,  and  Lehmann  could 
detect  no  effects  in  the  dog,  after  the  administration  of  155  G.  of  the 
carbonate  in  the  course  of  335  days,  although  a  considerable  amount 
of  the  metal  had  been  absorbed. 

In  workers  in  zinc,  a  curious  condition  known  as  brassfounders' 
ague,  is  occasionally  met  with.  It  is  ushered  in  by  a  sense  of  general 
discomfort  and  weakness,  with  more  or  less  pain  in  different  parts  of 
the  body ;  later  prolonged  rigors  and  shivering  are  followed  by  a  rapid 
acceleration  of  the  pulse,  coughing  and  soreness  of  the  chest,  and  head- 
ache. These  symptoms  give  place  to  profuse  perspiration,  and  the 
patient  sinks  into  a  sleep  from  which  he  awakes  in  ordinary  health. 
The  attacks  may  return  frequently,  and  seem  to  be  due  to  the  fumes 
of  zinc  which  escape  in  the  process  of  casting.  A  number  of  obscure 
nervous  conditions  have  also  been  described  as  arising  from  zinc  in 
workmen  in  brass  factories  and  bronze  works,  but  they  seem  to  be  ex- 
tremely rare,  and  it  is  questionable  whether  they  are  really  due  to  the 
zinc  or  to  its  impurities,  such  as  arsenic  and  lead. 

Action. — The  general  action  of  zinc  can  therefore  be  observed  only  when 
it  is  injected  intravenously,  or  hypodermically.  For  this  purpose,  the 
double  salts  alone  can  be  used,  as  the  ordinary  salts  precipitate  the  proteids 
of  the  blood  when  injected  into  a  vein,  and  cause  acute  irritation  when  ap- 
plied subcutaneously.  In  the  frog,  zinc  is  found  to  cause  weakness  and 
lessened  reflex  excitability,  and  the  heart  becomes  weak  and  inefficient,  ir- 
regular and  slow,  and  eventually  ceases  in  diastole.  The  action  seems  to  be 
exercised  chiefly  on  the  central  nervous  system  and  the  heart,  although  the 
voluntary  muscles  respond  more  weakly  to  the  electric  current  in  life,  and 
lose  their  irritability  entirely  soon  after  death.  Meihuizen  inferred  from  his 
experiments  that  the  zinc  salts  reduce  the  reflex  irritability  markedly  in 
the  frog,  but  he  used  an  irritant  salt  and  this  invalidates  his  results. 

In  mammals  the  intravenous  injection  of  zinc  causes  vomiting  and  diar- 
rhoea, weakness,  tremor,  and  paralysis  of  the  extremities  ;  and  the  stomach, 
intestine  and  heart  contain  small  haemorrhages.  The  blood-pressure  seems 
to  be  but  little  affected,  until  just  before  death,  but  the  pulse  is  slowed. 
Helpup  found  that  the  subcutaneous  injection  of  zinc  salts  induced  conges- 
tion and  parenchymatous  inflammation  of  the  kidney. 

Zinc  seems  therefore  to  depress  the  central  nervous  system,  and  to  a  less 
extent  the  heart  and  voluntary  muscles,  and  to  cause  irritation  and  conges- 
tion of  the  mucous  membrane  of  the  stomach  and  intestine,  and  inflamma- 
tion of  the  kidney.  The  fact  that  vomiting  occurs  from  the  intravenous  in- 
jection of  zinc  salts  might  seem  to  indicate  that  it  acts  directly  on  the 


ZINC.  685 

medullary  centre  for  vomiting,  but  may  more  probably  be  explained  by  the 
metal  inducing  inflammation  in  the  stomach.  These  effects  occur,  how- 
ever, only  when  the  metal  is  administered  by  way  of  the  blood  vessels  or 
subcutaneously. 

Zinc  has,  according  to  Grahe  and  Robert,  a  special  affinity  for  the  hemo- 
globin, with  which  it  forms  a  compound  (zinc-haemol),  but  its  administration 
has  no  effect  on  the  formation  of  haemoglobin. 

Lehmanu  found  that  of  the  zinc  absorbed  from  the  stomach  and  intestine, 
most  is  contained  in  the  liver  and  bile,  less  in  the  spleen,  kidney,  thyroid  and 
pancreas,  and  very  little  in  the  other  tissues.  Zinc  is  excreted  by  the  stom- 
ach and  intestinal  walls,  and  in  much  smaller  amounts  in  the  bile  and  urine. 

Locke  found  zinc  to  possess  a  poisonous  action  on  the  tadpole  and  tubifex 
when  present  in  traces  in  the  water  in  which  they  lived,  but  this  effect  was 
weaker  than  that  of  copper.  Eichter  states  that  zinc  is  less  poisonous  to 
fungi  than  copper,  and  very  weak  solutions  seem  to  promote  their  growth. 
The  zinc  salts  seem  to  be  in  general  much  weaker  than  those  of  copper,  which 
they  resemble  closely  in  other  respects. 

PREPARATIONS. 

Zincum  (U.  S.  P.),  metallic  zinc,  is  used  only  to  form  the  other  prepara- 
tions and  as  a  reagent. 

ZINCI  SULPHAS  (U.  S.  P.,  B.  P.)  (ZnSO4+  7H2O),  colorless,  transparent, 
odorless  crystals,  with  a  harsh,  astringent,  metallic  taste,  soluble  in  water, 
not  in  alcohol.  0.5-2  G.  (8-30  grs.),  as  emetic  ;  0.05-0.2  G.  (1-3  grs.),  in 
epilepsy. 

Zinci  Oxidum  (U.  S.  P.,  B.  P.)  (ZnO),  an  amorphous  white  powder  with- 
out odor  or  taste,  insoluble  in  water.  0.1-0.5  G.  (2-8  grs.). 

Zinci  Carbonas  Prsscipitatus  (U.  S.  P.),  Zinci  Carbonas  (B.  P.),  a  prepara- 
tion varying  somewhat  in  composition,  but  always  containing  some  oxide, 
which  it  resembles  in  appearance  and  solubility.  0.1-0.5  G.  (2-8  grs.). 

UNGUENTUM  ZINCI  OXIDI  (U.  S.  P.),  1  part  to  4  of  benzoinated  lard. 

UNGUENTUM  ZINCI  (B.  P.),  15  per  cent,  of  the  oxide. 

Zinci  Stearas  (U.  S.  P.). 

Unguentum  Zinci  Stearatis  (U.  S.  P. ),  50  per  cent. 

Unguentum  Zinci  Oleatis  (B.  P.). 

Zinci  Chloridum  (U.  S.  P.,  B.  P.)  (ZnCl2),  a  white  powder,  or  porcelain-like 
mass,  irregular,  or  moulded  into  pencils,  odorless  and  strongly  caustic,  very 
deliquescent,  and  soluble  in  water  and  alcohol. 

Liquor  Zinci  Chloridi  (U.  S.  P.,  B.  P.),  about  36  per  cent. 

Zinci  Acetas  (U  S  P    B.  P.)  (Zn(C,H,Of),  +  2H9O).     0.05-0.1  G.  (1-2  grs.). 

Zmci  Valeras  (U    S.  P.,  B.  P.)  (Zn(C5H9O2)2  +  2H.O).     0.05-0. 1  G. 

Zinci  Bromidum  (U.  S.  P.)  (ZnBr2).     0.05-0.1  G. 

Zinci lodidum  (U.  S.  P.)  (ZnI2).     0.05-0.1  G. 

Zmcitiulphocarbolas  (B.  P.),  Zinci  Phenolsulphonas  (U.  S.  P.)  (Zn(C  H  SO  ) 
-f  8H  O),   colorless  crystals  with  an  astringent  taste,  soluble  in  water  and  in 
Used  externally  in  1  per  cent,  solution.     (See  page  422.) 

Therapeutic  Uses.  — Zinc  sulphate  has  been  used  internally  as  an 
emetic,  but  not  so  widely  as  the  sulphate  of  copper,  although  it  is 
equally  efficient.  The  sulphate,  the  oxide  and  the  carbonate  have  been 
advised  in  the  treatment  of  various  brain  diseases,  such  as  epilepsy 
chorea  and  hysteria,  in  which  zinc  is  believed  to  act  as  a  sedative' 
Jixpenments  on  animals  and  on  healthy  persons  give  no  reason  to  be- 
lieve in  this  sedative  action,  and  clinicians  are  divided  as  to  its  useful- 
ness m  these  diseases,  but  there  is  some  support  for  the  treatment  The 
oxide  and  sulphate  are  seldom  employed  as  astringents  in  diarrhoea 

Externally,  the  zinc  preparations,  with  the  exception  of  the  chloride 


686  THE  HEAVY  METALS. 

are  used  as  astringents,  the  sulphate  being  applied  in  solution,  the 
oxide  and  carbonate  as  powders  or  as  ointments,  which  most  prefer  to 
the  oleate.  The  oxide  is  especially  useful  as  an  application  in  many  skin 
diseases.  Solutions  of  the  sulphate  are  used  as  an  eye  wash  (J  per  cent.) 
and  as  an  injection  in  gonorrhoea  (1-4  per  cent.).  In  the  last  case  it  is 
sometimes  formed  into  a  mixture  with  acetate  of  lead,  the  sulphate  of 
lead  which  results  being  credited  with  some  astringent  action  and  not 
being  washed  off  so  readily  from  the  diseased  surface.  The  sulpho-car- 
bolate  is  also  used  as  a  urethral  injection,  and  the  salicylate  and  the 
sulpho-iodolate  of  zinc  have  also  been  introduced  as  astringent  and  anti- 
septic applications. 

The  chloride  of  zinc  differs  from  the  other  salts  in  being  a  powerful  caus- 
tic, and  is  used  as  a  paste  or  in  pencil  form  to  destroy  malignant  growths,  or 
in  chancres  and  gangrenous  sores.  It  produces  a  white  eschar  and  is  said  to 
be  less  liable  to  spread  over  the  surface  than  potash,  but  penetrates  the  epi- 
dermis with  difficulty,  and  it  is  therefore  advisable  to  destroy  this  with  pot- 
ash or  a  blister  before  applying  the  caustic.  It  is  sometimes  mixed  with 
flour  or  dried  gypsum  and  water  to  a  paste  (Canquoin's  paste),  when  a  less 
active  caustic  is  desired.  Its  use  is  much  more  restricted  at  the  present 
time  than  formerly,  when  there  was  greater  apprehension  of  the  minor  surgi- 
cal operations,  but  it  has  been  recommended  as  a  caustic  and  disinfectant 
application  in  inoperable  cancer.  In  very  dilute  solution  it  has  been  applied 
as  a  disinfectant  lotion  or  injection  (1  in  5,000).  Burnett's  disinfecting  solu- 
tion (a  somewhat  stronger  solution  than  the  official  liquor)  is  used  to  disin- 
fect faeces  and  urinals,  and  the  liquor  of  the  pharmacopceia  may  be  employed 
for  the  same  purpose.  It  has  frequently  given  rise  to  severe  corrosive 
poisoning  from  being  swallowed  accidentally  or  suicidally. 

The  acetate  of  zinc  acts  in  the  same  way  as  the  sulphate  and  may  be  used 
for  the  same  purpose.  The  valerianate  and  bromide  have  been  introduced 
with  the  intention  of  combining  the  action  of  zinc  with  that  of  valerian  or 
bromide  in  hysteria  and  epilepsy,  but  valerianic  acid  is  entirely  devoid  of 
any  action  on  the  brain  (see  Valerian,  page  74)  and  the  bromide  is  given  in 
too  small  doses  to  exert  any  influence.  The  iodide  is  used  in  a  similar  at- 
tempt to  combine  the  astringent  effects  of  zinc  and  the  specific  action  of 
iodides,  but  is  open  to  the  same  objection.  The  action  of  the  phosphide  is 
practically  identical  with  that  of  phosphorus.  Poisoning  with  zinc  is  treated 
in  the  same  way  as  that  with  copper. 

BIBLIOGRAPHY. 

Harnack     Arch.  f.  exp.  Path.  u.  Pharm.,  iii.,  p.  53. 

Bucholtz.     Ibid.,  iv.,  p.  64. 

Helpup.     Inaug.  Diss.,  Greifswald,  1889.     Deutsch.  med.  Woch.,  1889,  p.  782. 

Sacher.     Arbeit,  a.  d.  pharmak.  Instit.  zu  Dorpat,  ix.,  p.  88. 

Grahe.     Ibid.,  ix.,  p.  155. 

Lehmann.     Arch.  f.  Hygiene,  xxviii.,  p.  291. 

Morner.     Ibid.,  xxxiii.,  p.  160. 

Jacobj.     Arb.  a.  d.  k.  Gesundheitsamte,  xv.,  p.  204. 

Volcker.     Beitrage  z.  klin.  Chirurg.,  xxvii.,  p.  592. 

Eichter.     Centralbl.  f.  Bacteriologie  (II.),  vii.,  p.  417. 

VII.     SILVER. 

The  only  salt  of  silver  used  at  all  extensively  in  medicine  is  the 
nitrate,  which  is  caustic,  astringent  and  antiseptic.  Added  to  solutions 
of  proteids,  it  forms  a  heavy  precipitate  of  albuminate,  which  is  at 


SILVER.  687 

first  white  in  color  but  turns  darker  in  the  light  as  the  silver  is  re- 
duced, and  which  is  soluble  in  the  presence  of  chlorides. 

Symptoms.  —  In  dilute  solution  silver  is  a  slight  irritant  to  the  skin, 
and  causes  redness  and  itching  only,  but  more  concentrated  solutions 
blister,  and  the  solid  nitrate  of  silver  causes  an  eschar,  which  is  at  first 
white,  but  later  turns  black  from  the  reduction  of  the  silver  in  light. 
On  the  mucous  membrane,  dilute  solutions  act  as  astringents,  but  con- 
centrated cause  irritation  and  corrosion.  The  caustic  action  of  silver 
does  not  extend  so  deeply  as  that  of  some  other  metals,  such  as  mer- 
cury, because  the  penetration  of  the  metal  is  limited  by  the  membrane 
of  silver  albuminate  formed.  On  the  other  hand,  the  silver  salts  are 
more  irritant  than  those  of  lead. 

Dilute  solutions  of  silver  nitrate  are  said  to  contract  the  vessels 
when  they  are  applied  locally,  and  this  may  be  correct  under  some 
circumstances,  but  if  irritation  is  induced,  the  vessels  are  certainly 
dilated.  The  astringent  action  is  to  be  attributed  not  to  any  action  on 
the  vessels,  but  to  the  formation  of  a  protective  layer  of  coagulated 
albumin. 

In  acute  silver  poisoning  from  the  ingestion  of  silver  nitrate,  the 
symptoms  are  those  of  severe  gastro-intestinal  irritation  and  corrosion. 
Burning  pain  is  felt  in  the  throat  and  stomach,  and  is  followed  by 
nausea  and  vomiting  and  often  by  purging.  The  mouth  is  covered 
with  a  grayish-white  membrane,  which  turns  darker  after  a  time,  but 
this  is  absent  if  the  poison  be  swallowed  in  the  solid  form,  as  has  hap- 
pened sometimes.  The  corrosion  of  the  stomach  and  intestine  causes 
collapse,  with  weak  pulse,  shallow  respiration  and  pinched  features,  and 
this  may  be  followed  by  coma,  convulsions  and  death.  The  throat, 
stomach  and  intestine  presented  the  ordinary  appearances  of  acute  cor- 
rosive poisoning  in  one  case  in  which  an  autopsy  was  performed. 

Action.  —  The  symptoms  of  acute  poisoning  are  due  to  the  local  action, 
and  present  no  features  suggesting  that  silver  is  absorbed  and  causes  general 
poisoning.  The  action  of  silver  after  absorption  has,  however,  been  investi- 
gated in  animals  poisoned  by  subcutaneous  or  intravenous  injection.  The 
nitrate,  owing  to  its  coagulating  properties,  is  unsuitable  for  this  purpose, 
and  the  hyposulphite  of  sodium  and  silver,  or  a  solution  of  the  albuminate 
has  therefore  been  used.  In  mammals  the  central  nervous  system  is  the 
chief  seat  of  action,  especially  the  medulla  oblongata,  which  seems  to  be 
stimulated  at  first,  for  the  blood-pressure  rises  and  the  pulse  is  somewhat 
slow,  owing  to  increased  activity  of  the  vaso-motor  and  vagus  centres. 
Later  the  blood-pressure  falls,  and  the  respiration  becomes  slow  and  labored, 
and  eventually  ceases  from  paralysis  of  the  centre.  Gaethgens  asserts  that 
the  diaphragm,  and  eventually  the  other  striated  muscles  are  paralyzed  soon 
afterwards.  The  heart  is  comparatively  little  affected,  and  often  continues 
to  beat  some  time  after  the  respiration  has  stopped.  In  less  acute  poison- 
ing, when  the  animal  survives  the  injection  for  several  hours  or  days,  a 
marked  increase  in  the  bronchial  secretion,  culminating  in  oedema  of  the 
lungs,  has  been  noted  ;  no  satisfactory  explanation  of  this  has  been  advanced, 
but  it  does  not  seem  due  to  cardiac  inefficiency  and  occurs  also  when  the 
excised  lung  is  perfused  with  blood  containing  silver.  Congestion  and 
ecchymoses  are  found  in  the  stomach  and  intestine,  and  some  authors  men- 
tion ulceration  of  these  mucous  membranes.  Cohnstein  found  that  small 


688  THE  HEAVY  METALS. 

quantities  of  silver  salts  injected  intravenously  cause  some  increase  in  the 
urine  for  a  time,  but  that  larger  quantities  are  followed  by  albuminuria. 

In  cold-blooded  animals  and  in  invertebrates,  silver  preparations  are  said 
to  cause  violent  convulsions,  resembling  those  of  strychnine  and  followed  by 
general  paralysis.  The  heart  is,  according  to  one  investigator,  little  affected, 
according  to  another,  it  is  found  in  diastole. 

The  general  action  of  silver  is  thus  apparently  directed  first  of  all  against 
the  medulla  oblongata,  the  rest  of  the  central  nervous  system  being  affected 
to  a  less  extent.  The  mucous  membrane  of  the  stomach  and  intestine  is 
acted  on,  as  by  most  heavy  metals,  and  the  kidney  is  also  liable  to  irritation. 
(Edema  of  the  lungs  occurs  frequently. 

Chronic  Poisoning. — There  is  no  evidence  that  in  acute  poisoning  in 
man  any  considerable  amount  of  the  metal  is  absorbed  from  the  stomach 
and  intestine.  When  silver  is  given  for  prolonged  periods,  however,  some 
is  absorbed,  although  probably  only  a  minute  fraction  of  that  actually 
swallowed.  In  the  stomach  small  quantities  of  soluble  silver  salts  are 
probably  changed  to  the  chloride  and  albuminate,  but  the  form  in 
which  the  metal  is  absorbed  has  proved  a  subject  of  dispute.  It  seems 
to  be  taken  up  in  solution,  for  none  of  it  is  found  in  the  epithelium  of 
the  stomach  and  intestine,  and  some  of  it  may  circulate  in  the  blood 
in  a  soluble  form  for  a  short  time.  But  the  greater  proportion  is  very 
soon  thrown  down  in  the  form  of  minute  granules,  which  were  for- 
merly believed  to  be  metallic  silver,  but  which  have  more  recently 
been  said  to  be  one  of  its  organic  compounds.  The  formation  of  this 
pigment  is  quite  different  from  the  reduction  of  silver  in  sunlight,  for 
it  occurs  in  complete  darkness.  The  change  apparently  takes  place  in 
the  cells,  especially  in  the  leucocytes,  but  the  granules  are  afterwards 
extruded  into  the  surrounding  fluid.  They  are  found  in  the  connective 
tissues  of  the  body  chiefly,  and  when  present  in  quantity,  give  a  dark 
color  to  the  skin  and  mucous  membranes.  This  pigmentation  (Ar- 
gyria)  was  much  commoner  formerly  than  at  the  present  time,  but 
several  cases  have  been  described  quite  recently.  The  chief  source  of 
chronic  silver  poisoning  or  argyria  was  formerly  the  treatment  of 
epilepsy  with  the  nitrate.  More  recently  it  has  occurred  in  the  makers 
of  artificial  pearls,  who  use  silver  as  a  pigment. 

Local  argyria  is  sometimes  met  with  from  the  prolonged  application 
of  silver  nitrate  to  the  eye  or  throat,  when  it  tints  the  eyelids  and 
mouth,  and  from  working  with  silver,  when  the  hands  are  permanently 
blackened  from  the  granules  being  forced  into  the  skin. 

The  deposit  of  the  silver  in  the  skin  gives  it  a  darker  color,  varying 
from  light  gray  in  mild  cases  to  a  darker  slate  shade  after  more  pro- 
longed use.  It  is  generally  distributed  all  over  the  body,  but  in  some 
cases  has  been  especially  marked  in  the  face,  and  it  is  said  to  begin  in 
the  gums,  where  it  causes  a  dark,  slate-colored  line  somewhat  resem- 
bling the  lead  line.  In  the  skin  it  is  found  in  the  corium,  not  in  the 
epidermis.  The  deposit  and  the  dark  color  extend  throughout  the 
alimentary  canal  and  the  respiratory  passages,  the  granules  occurring 
in  the  connective  tissue,  particularly  in  the  intestinal  villi,  and  not  in 
the  epithelium.  The  glomeruli  of  the  kidneys,  the  connective  tissue 
of  the  liver  and  spleen,  the  choroid  plexus,  the  tunica  intima  of  the 


SILVER.  689 

aorta,  the  serous  membranes,  and  the  mesenteric  lymph  glands  contain 
more  of  the  deposit  than  other  organs.  The  pigmentation  is  not  ac- 
companied by  any  other  symptom  of  importance,  and  the  victims  live 
to  old  age  without  suffering  from  the  chronic  poisoning  in  any  way, 
except  from  the  annoyance  induced  by  the  change  in  color. 

Argyria  is  quite  incurable,  although  many  attempts  have  been  made 
to  remove  it.  Iodide  has  been  tried,  for  the  most  part  without  effect, 
and  blistering  is  equally  valueless  as  the  pigment  lies  deeper  than  the 
epidermis.  The  only  known  solvent  of  the  granules  is  cyanide  of 
potassium,  and  of  course  this  is  inadmissible  owing  to  its  powerful 
poisonous  action. 

Argyria  has  been  induced  in  animals  by  prolonged  treatment  with 
small  doses  of  silver  salts,  though  the  pigment  is  not  found  in  the  skin 
in  them,  but  in  the  duodenal  mucous  membrane  and  the  mesentery 
attached  to  it,  the  mesenteric  lympii  glands,  the  spleen  and  liver.  A 
still  more  limited  area  of  argyria  has  been  caused  in  animals  recently 
by  administering  for  a  few  weeks  the  glycyrrhizinate  of  silver.  It  is 
not  unlikely  that  more  prolonged  administration  would  lead  to  other 
organs  and  perhaps  the  skin  being  involved.  A  deposit  of  silver  pig- 
ment has  also  been  induced  in  animals  by  a  single  injection  of  a  non- 
irritant  preparation  into  a  vein,  or  into  the  subcutaneous  tissue.  Here 
the  silver  is  found  at  first  in  the  liver  capillaries,  the  glomeruli  of  the 
kidney,  the  intestine  and  the  bone  marrow,  but  is  afterwards  taken  up 
by  the  leucocytes,  and  carried  to  all  the  organs  of  the  body.  Various 
symptoms  of  chronic  poisoning  quite  apart  from  argyria  have  been  de- 
scribed in  animals  from  prolonged  treatment  with  silver,  but  it  would 
seem  that  they  were  due  not  to  the  direct  action  of  the  drug,  but  to  the 
continued  irritation  of  the  stomach  and  intestine,  as  they  were  entirely 
absent  when  less  irritant  preparations  and  greater  care  in  administra- 
tion were  used. 

In  man  it  seems  likely  that  most  of  the  silver  passes  through  the 
alimentary  canal  unabsorbed,  and  that  the  small  proportion  taken  up 
by  the  tissues  is  precipitated  and  remains  embedded  in  them  indefi- 
nitely, for  the  pigmentation  remains  unchanging  in  its  depth,  and  there 
is  therefore  no  reason  to  suppose  that  any  of  the  silver  is  eliminated. 

In  animals,  however,  some  of  the  silver  injected  hypodermically  or 
intravenously  is  excreted  by  the  epithelium  of  the  alimentary  canal. 
None  appears  in  the  urine.  In  the  frog,  silver  injected  hypodermically 
is  all  excreted  by  the  epithelium  of  the  tongue,  is  swallowed,  and 
passes  out  in  the  faeces.  No  other  poison  is  known  to  be  eliminated 
by  this  channel. 

Silver  nitrate  is  a  powerful  antiseptic,  partly  from  its  action  in  co- 
agulating the  proteids  of  the  micro-organisms,  partly  from  the  specific 
effects  of  the  metal,  as  is  shown  by  the  fact  that  the  albuminate  of  sil- 
ver is  also  an  active  disinfectant. 
44 


690  THE  HEAVY  METALS. 

PREPARATIONS. 

Ar genii  Nitras  (U.  S.  P.,  B.  P.)  (AgNO?),  colorless  crystals  which  be- 
come gray  or  grayish-black  on  exposure  to  light  in  the  presence  of  organic 
matter,  with  a  bitter,  caustic,  strongly  metallic  taste,  very  soluble  in  water, 
less  so  in  alcohol.  0.01-0.03  G.  (£-£  gr.)  in  pills  made  up  with  kaolin. 

ARGENTI  NITRAS  Fusus  (U.  S.  P.),  moulded  nitrate  of  silver,  lunar  caus- 
tic— a  white,  hard  solid,  generally  cast  in  the  form  of  pencils. 

ARGENTI  NITRAS  INDURATTJS  (B.  P.),  toughened  caustic,  a  silver  nitrate 
fused  with  5  per  cent,  of  nitrate  of  potassium. 

Ar  genii  Nitras  Mitigatus  (B.  P.,  U.  S.  P.),  mitigated  caustic,  consists  of  one 
part  of  nitrate  of  silver  and  two  parts  of  nitrate  of  potassium  fused  into  rods 
like  lunar  caustic. 

Argenti  Ozidum.(U.  S.  P.,  B.  P.)  (Ag2O),  a  heavy,  brownish-black  powder, 
odorless  and  having  a  metallic  taste,  very  little  soluble  in  water.  0.03-0.1 
G.  (i-2  grs.). 

The  silver  preparations  ought  to  be  kept  in  dark  amber-colored  bottles,  in 
order  to  prevent  their  being  reduced  by  light,  and  ought  not  to  be  prescribed 
with  organic  matter,  which  rapidly  reduces  them. 

Therapeutic  Uses.  —  Silver  nitrate  pills  have  been  recommended  in 
some  forms  of  dyspepsia  and  vomiting,  and  in  gastric  ulcer,  and  have 
also  been  used  as  astringents  in  diarrhoea,  but  generally  with  little 
benefit.  A  very  ancient  use  of  silver  oxide,  and  more  recently  of  the 
nitrate,  is  that  in  the  treatment  of  epilepsy,  chorea,  tabes  and  various 
other  nervous  diseases.  This  dates  from  the  Arabs,  and  is  said  to 
have  originated  from  the  astrological  medicine  of  that  period,  which 
taught  that  nervous  diseases  were  especially  affected  by  the  phases  of 
the  moon,  which  was  associated  with  silver  in  their  system  (hence, 
lunar  caustic,  lunacy).  Clinical  experience  shows  that  silver  is  of  no 
benefit  in  epilepsy,  and,  in  fact,  it  is  improbable  that  silver  reaches  the 
central  nervous  system  in  any  other  form  than  inert  granules.  This 
use  of  silver  very  often  gave  rise  to  argyria  without  benefiting  the  pa- 
tient, about  15—30  G.  proving  sufficient  to  cause  marked  pigmentation. 

Externally,  silver  nitrate  is  employed  very  extensively,  the  sticks  of 
lunar  caustic  being  used  to  destroy  warts  and  other  small  skin  growths, 
to  arrest  capillary  haemorrhage,  to  destroy  the  false  membranes  of 
diphtheria,  and  for  other  similar  purposes.  Where  a  milder  caustic  is 
required  the  mitigated  caustic  is  used  instead  of  ordinary  lunar  caus- 
tic. A  solution  of  2-5  per  cent,  may  also  be  applied  to  cauterize  chan- 
cres and  indolent  ulcers,  and  one  of  1-2  per  cent,  may  be  painted  on 
mucous  membranes  as  an  irritant  antiseptic.  A  solution  of  common  salt 
is  then  used  to  wash  the  part,  in  order  to  remove  the  excess  of  silver. 
In  ophthalmia,  especially  of  the  infectious  form,  a  solution  of  1—2  per 
cent,  is  extremely  valuable,  and,  in  fact,  a  routine  treatment  in  some 
lying-in  hospitals  is  to  wash  the  eyes  of  the  infant  with  this  solution 
immediately  after  birth  as  a  prophylactic  measure  to  prevent  oph- 
thalmia. A  solution  of  this  strength  is  only  to  be  used  by  the  surgeon 
himself,  and  the  eye  should  be  washed  out  with  a  salt  solution  at 
once.  A  more  dilute  solution  (J-J  per  cent.)  may  be  used  as  a  lotion 
for  the  eye  more  frequently,  may  be  applied  to  extensive  denuded 
surfaces,  as  burns,  and  is  often  thrown  into  the  rectum  in  chronic 


SILVER.  691 

dysentery.  In  gonorrhoea  the  nitrate  of  silver,  one  part  in  500-2000 
of  water,  is  used  as  an  injection,  and  is  found  to  have  great  value,  de- 
stroying the  gonococci  and  promoting  healing.  Very  much  stronger 
solutions  (up  to  5  per  cent.)  have  been  used  to  abort  the  disease  in  its 
onset,  but  cause  great  pain. 

The  precipitation  of  silver  nitrate  by  proteids  and  chlorides  confines  its 
disinfectant  action  to  narrower  limits  than  those  of  some  other  antiseptics, 
and  this  has  led  to  the  introduction  of  a  number  of  other  compounds,  which 
are  less  easily  dissociated  and  accordingly  less  liable  to  be  thrown  out  of  so- 
lution. Thus  argentamine,  a  ten  per  cent,  solution  of  silver  phosphate  in 
ten  per  cent,  ethylendiamine  solution,  has  been  used  in  gonorrhoea  diluted 
to  1 : 1,000-5,000,  in  the  eye  in  five  per  cent,  solution.  It  penetrates  better 
than  silver  nitrate,  but  the  alkaline  diamine  renders  it  somewhat  irritating. 
Another  recent  product  is  argonin,  which  is  a  combination  of  casein  and 
silver,  is  soluble  in  water,  and,  like  argentamine,  is  not  precipitated  by 
chlorides  nor  by  albumin  ;  it  is  a  somewhat  weaker  antiseptic  than  the  nitrate 
and  argentamiue.  The  lactate  of  silver,  actol,  and  the  citrate,  itrol,  have 
also  been  used  as  antiseptics.  Actol  is  soluble  in  water,  and  resembles  the 
nitrate  in  coagulating  proteids,  while  itrol,  on  the  other  hand,  is  practically 
insoluble  (1  to  3,800  water).  The  former  is  used  in  solution  (i  per  cent.),  the 
latter  as  a  disinfecting  powder  in  wounds.  Actol  and  argonin  have  been 
shown  to  have  very  considerable  disinfectant  power  in  test-tube  cultures,  and 
actol  lessens  the  putrefaction  in  the  bowel  and  constipates  to  some  extent, 
but  argonin  has  no  effect  on  the  intestinal  microbes.  Protargol,  largin,  and  many 
other  compounds  of  silver  have  been  introduced,  but  all  of  these  have  been 
replaced  in  the  last  few  years  by  Crede' s  colloid  silver  ( Collar gol),  which  is  metallic 
silver  in  colloid  form,  which  may  be  suspended  in  water  (4  per  cent. )  or  in  oint- 
ment (10-15  per  cent.).  It  is  said  to  be  efficient  as  a  disinfectant  in  the  same 
conditions  as  have  hitherto  been  treated  with  the  nitrate  and  to  be  practically 
devoid  of  the  irritant  and  corrosive  action  of  the  latter.  Attempts  have  been 
made  to  use  it  by  hypodermic  or  intravenous  injection  in  general  septicaemia,  but 
the  earlier  claims  of  its  advocates  that  it  was  of  value  as  an  antiseptic  in  consti- 
tutional diseases  have  proved  to  have  no  more  foundation  than  the  similar  state- 
ments in  regard  to  other  antiseptics.  (See  pages  393-396.) 

Silver  preparations  ought  not  to  be  used  for  long  periods,  as  argyria  has 
been  induced  in  three  months  and  after  the  use  of  15-30  G.  (J-l  oz.)  of  the 
nitrate. 

In  cases  of  poisoning  with  silver  nitrate,  eggs,  milk  and,  above  all,  com- 
mon salt  solution  are  indicated  to  form  insoluble  compounds.  In  argyria 
no  improvement  can  be  expected,  though  the  iodide  of  potassium  may  be 
tried. 

BIBLIOGRAPHY. 

Bogoslowsky.     Virchow's  Arch.,  xlvi.,  p.  409. 

Jacobi.     Arch.  f.  exp.  Path.  u.  Pharm.,  viiL,  p.  198. 

Rozsahegzi.     Ibid.,  ix.,  p.  289. 

Cohnstein.     Ibid.,  xxx.,  p.  129. 

Loew.     Pfliiger's  Arch.,  xxxiv.,  pp.  596,  602. 

Schubert.     Zts.  f.  Heilkunde,  xvi.,  p.  341. 

Samqjloff.     Arb.  a.  d.  pharm.  Instit.  Dorpat,  ix.,  p.  27. 

Gerschun.     Ibid.,  x.,  p.  154. 

Tschisch.     Virchow's  Arch.,  c.,  p.  147. 

Crete.     Arch.  f.  klin.  Chirurg.,  lv.,  p.  861. 

Mosse.     Zts.  f.  phys.  Chem.,  xxiii.,  p.  160. 

Liebrecht.     Therap.  Monatsheft,  1895,  p.  306. 

Van  der  Does.     Zts.  f.  phys.  Chem.,  xxiv.,  p.  351. 

Athanasiu.     Journ.  de  Physiol.,  iii.,  p.  163. 

Bid.     Ztschr.  f.  physikal.  Chem.,  xl.,  p.  513. 


692  THE  HEAVY  METALS. 


VIII.     BISMUTH. 

The  insoluble  salts  of  bismuth,  in  especial  the  subnitrate,  have  long 
enjoyed  a  reputation  in  the  treatment  of  gastric  and  intestinal  irrita- 
tion, and  have  more  recently  been  advised  in  surgery  as  applications 
to  granulating  wounds. 

Symptoms.  —  Taken  in  therapeutic  doses,  the  subnitrate  induces  no 
marked  symptoms,  even  after  prolonged  use.  It  has  little  or  no  taste, 
and  passes  through  the  stomach  and  intestine  for  the  most  part  unab- 
sorbed.  It  is  said  to  increase  the  peristalsis  of  the  stomach  and  the 
secretion  of  mucus,  but  it  may  be  questioned  whether  it  has  more  effect 
here  than  any  other  heavy  powder.  In  the  intestine  it  is  said  to  have 
some  effect  in  increasing  the  leucocytes  of  the  blood,  and  often  causes 
some  constipation.  It  gives  the  stools  a  black  color,  which  is  gener- 
ally believed  to  be  due  to  the  formation  of  the  sulphide  of  bismuth, 
but  which  Quincke  ascribes  to  the  reduction  of  the  subnitrate  in  the 
intestine. 

Very  little  of  the  bismuth  swallowed  is  absorbed,  but  several  au- 
thorities have  found  traces  in  the  urine  of  patients  treated  with  it  in- 
ternally so  that  some  evidently  passes  into  the  blood  under  certain 
unknown  conditions.  Enormous  quantities  have  been  administered 
internally  without  any  symptoms  of  poisoning  being  elicited,  but  in  one 
or  two  cases  some  stomatitis  has  been  remarked,  while  in  other  in- 
stances large  concretions  of  bismuth  have  been  found  in  the  stomach 
and  bowel.  Some  of  the  older  writers  describe  serious  poisoning  from 
bismuth,  but  this  was  not  due  to  the  drug  itself,  but  to  the  lead,  arsenic, 
or  antimony  with  which  it  was  contaminated.1  As  long  as  bismuth 
was  given  only  internally,  no  serious  symptoms  arose  from  its  action, 
and  in  fact  any  effects  whatever  beyond  slight  constipation  were  ex- 
tremely rare.  But  since  its  use  was  extended  to  wounded  surfaces, 
several  cases  of  serious  intoxication  have  occurred.  The  symptoms 
are  salivation,  swelling  of  the  gums,  tongue,  and  throat,  pain  and 
difficulty  in  swallowing,  black  spots  in  the  mouth  and  throat,  and  gan- 
grene of  the  soft  palate  and  other  parts  of  the  mucous  membrane  of  the 
mouth.  Vomiting,  diarrhoea  and  albuminuria  follow,  but  the  pa- 
tients generally  recover  when  the  dressing  is  removed  from  the 
wound.  In  these  cases  much  less  bismuth  is  applied  than  is  often 
prescribed  for  internal  use,  so  that  it  would  appear  that  it  is  absorbed 
more  rapidly  from  granulating  surfaces  than  from  the  mucous  mem- 
branes, or  that  what  is  absorbed  from  the  stomach  and  intestine  is 
prevented  by  the  liver  from  reaching  the  general  circulation. 

Action. — The  general  action  of  bismuth  has  been  studied  in  animals  by  the 
subcutaneous  or  intravenous  injection  of  the  double  salts,  such  as  the  tartrate  of 
bismuth  and  sodium.  In  frogs  the  symptoms  are  those  of  stimulation  of  the 

1 A  symptom  formerly  noted  in  cases  treated  with  bismuth  was  an  extremely  dis- 
agreeable odor  in  the  breath,  but  this  has  been  shown  to  be  due  to  the  presence  of 
tellurium  in  the  preparation. 


BISMUTH.  693 

spinal  cord  and  medulla  oblongata,  followed  by  depression  and  paralysis.  The 
stimulation  induces  tonic  convulsions,  which  are  separated  by  periods  in  which 
the  frog  is  at  first  apparently  normal,  but  in  which  symptoms  of  depression  and 
paralysis  appear  later.  The  peripheral  nerves  and  muscles  and  the  heart  are 
little  affected. 

In  mammals  also,  large  doses  act  chiefly  on  the  central  nervous  system.  The 
respiration  is  accelerated,  the  heart  slowed,  and  violent  clonic  and  tonic  convul- 
sions follow  at  short  intervals,  during  which  the  movements  are  weak  and  inco- 
ordinated.  Toward  the  fatal  issue  of  the  injection  the  heart  often  ceases  entirely 
for  some  time,  and  then  regains  its  former  rhythm  quite  suddenly.  The  blood- 
pressure  falls,  partly  owing  to  the  weakness  of  the  heart,  partly  from  depression 
of  the  vaso-motor  centre.  In  some  animals  the  respiration  ceases  before  the 
heart ;  in  others,  the  sequence  is  reversed.  The  heart  seems  to  be  affected 
directly,  for  division  or  paralysis  of  the  vagus  nerves  does  not  alter  the  effects. 

Smaller  quantities  injected  intravenously  or  subcutaneously  into  mammals 
induce  a  more  chronic  form  of  intoxication,  which  resembles  that  seen  in  man. 
The  earliest  symptoms  are  loss  of  appetite,  vomiting  and  diarrhoea,  salivation 
and  stomatitis  with  ulceration  of  the  gums,  tongue,  and  buccal  mucous  mem- 
brane. Weakness,  slowness  and  incoordination  of  the  movements  follow,  and 
except  in  very  few  chronic  cases,  tetanic  convulsions  occur  at  intervals.  The 
urine  contains  albumin  and  casts.  The  weakness  gradually  deepens  into  com- 
plete paralysis  and  the  animal  dies,  generally  without  convulsions.  The  heart 
seems  little  affected  in  the  chronic  intoxication,  but  the  blood-pressure  is  low 
from  the  intestinal  irritation  and  general  collapse. 

Besides  the  stomatitis  and  ulceration  of  the  mouth,  the  post-mortem  appear- 
ances in  chronic  bismuth  poisoning  in  animals  consist  in  some  congestion,  inflam- 
mation and  necrosis  in  the  kidney,  and  an  intense  black  coloration  of  the  caecum 
and  the  upper  part  of  the  large  intestine.  This  pigmentation  is  limited  very 
exactly  by  the  ileocsecal  valve,  and  extends  throughout  the  thickness  of  the 
bowel  wall.  The  mucous  membrane  may  also  be  necrosed  in  places,  and  ulcers 
and  haemorrhages  are  met  with  in  it.  The  black  coloration  is  due  to  a  deposit 
of  bismuth  sulphide  on  the  mucous  membrane,  and  in  the  capillary  vessels  and 
lymph  spaces.  Meyer  and  Steinfeld  found  that  bismuth  is  excreted  all  along  the 
alimentary  canal,  but  in  larger  quantities  in  the  caecum  and  large  intestine  than 
elsewhere,  and  they  ascribe  the  ulceration  to  the  precipitation  of  the  sulphide  in 
the  vessels  and  the  consequent  arrest  of  the  blood  current.  When  sulphide  solu- 
tion was  artificially  introduced  into  the  stomach  and  small  intestine,  bismuth 
caused  necrosis  and  ulceration  here  also,  so  that  there  is  considerable  support  for 
this  view. 

They  found  bismuth  to  be  stored  in  considerable  quantity  in  the  liver,  and  to 
be  excreted  by  the  urine,  stomach  and  intestine,  but  especially  by  the  caecum  and 
large  bowel.  It  has  been  found  in  the  saliva  by  other  observers,  and  perhaps 
in  traces  in  the  milk,  although  the  last  is  not  satisfactorily  established. 

The  action  of  bismuth  in  acute  poisoning  in  animal  experiments  seems  there- 
fore to  be  exerted  on  the  medulla  and  spinal  cord,  to  a  less  extent  on  the  heart, 
while  in  chronic  intoxication  the  organs  affected  are  those  by  which  it  is  excreted 
— the  mouth,  kidney,  large  intestine,  and  caecum. 

PKEPAKATIONS. 

BISMUTHI  SUBNITRAS  (U.  S.  P.,  B.  P.),  white  bismuth,  Magisterium  Bis- 
muthi,  bismuth  oxynitrate,  a  heavy  white  powder  odorless  and  almost  taste- 
less, insoluble  in  water  or  alcohol  but  soluble  in  nitric  or  hydrochloric  acid. 
It  consists  of  a  mixture  of  the  hydrate  and  subnitrate  of  bismuth  in  varying 
proportions.1  0.3-2  G.  (5-30  grs.),  in  powder  or  suspended  in  water. 

1  The  B.  P.  defines  this  preparation  as  bismuthoxynitrate  (BiONO3H2O),  but  some 
hydrate  is  almost  invariably  present. 


694  THE  HEAVY  METALS. 

BismutU  Subcarbonas  (U.  S.  P.),  Bismuthi  Carbonas  (B.  P.),  bismuth  oxy- 
carbonate,  a  white  or  pale  yellowish -white  powder,  varying  in  composition, 
odorless,  tasteless,  insoluble  in  water  or  alcohol.  0.3-2  G.  (5-30  grs.)  in 
powder. 

Trochiscus  Bismuthi  Compositus  (B.  P.) ;  each  contains  2  grs.  of  bismuth 
oxycarbonate  along  with  the  carbonates  of  magnesia  and  of  lime. 

Bismuthi  Salicy'las  (B.  P.),  Bismuthi  Subsalicylas  (U.  S.  P.),  the  salicylate  or 
oxysalicylate  of  bismuth,  is  a  white,  amorphous  powder,  insoluble  in  water. 
5-20  grs. 

Bismuthi  Oxidum  (B.  P.)  (Bi2O3),  a  slightly  brownish-yellow  powder,  in- 
soluble in  water.  5-20  grs. 

Bismuthi  Citras  (U.  S.  P.)  (BiC6H5O7),  a  white  powder,  odorless,  tasteless, 
insoluble  in  water  or  alcohol,  used  only  to  form 

Bismuthi  et  Ammonii  Citras  (U.  S.  P.),  small,  shining,  translucent  scales, 
odorless,  but  with  a  slightly  acidulous  and  metallic  taste,  and  becoming 
opaque  on  exposure  to  the  air,  very  soluble  in  water,  less  so  in  alcohol.  0.1- 
0.3  G.  (2-5  grs.). 

Liquor  Bismuthi  et  Ammonii  Citratis  (B.  P.)  contains  the  equivalent  of  5 
per  cent,  of  bismuth  oxide.  £-1  fl.  dr. 

Bismuthi  Subgallas  (U.  S.  P.),  0.25  G.  (4  grs.),  forms  a  white  or  nearly  white 
powder,  insoluble  in  water,  tasteless  and  odorless. 

Therapeutic  Uses.  —  Bismuth  has  been  used  chiefly  in  gastric  catarrh 
and  ulcer,  and  has  often  been  looked  upon  as  a  specific  in  the  last 
affection,  though  it  acts  simply  as  a  protective  powder  with  perhaps 
some  astringent  properties.  It  has  been  found  that  when  swallowed 
it  is  at  first  deposited  in  the  most  dependent  part  of  the  stomach,  but 
is  later  distributed  evenly  over  the  surface,  and  forms  a  continuous 
sheet  over  any  ulceration,  which  it  thus  protects  from  mechanical  injury 
from  the  food,  and  also  from  the  chemical  action  of  the  gastric  juice. 
The  subnitrate  is  the  only  one  of  the  official  preparations  largely  used 
for  this  purpose,  and  is  generally  administered  in  quantities  of  2-3  G. 
(30-45  grs.)  per  day  in  powder.  Recently  the  use  of  much  larger 
quantities  (10-15  G.,  150—250  grs.,  per  day)  has  been  recommended. 
Bismuth  has  also  been  used  in  diarrhoaa  for  its  astringent  and  protective 
action  on  the  intestine,  which  is  again  due  to  its  being  deposited  on  the 
mucous  membrane  and  acting  as  a  mechanical  coating  over  irritated 
surfaces. 

The  subnitrate  has  been  advised  in  surgery  as  an  antiseptic,  astrin- 
gent powder  to  replace  iodoform.  It  is  true  that  it  is  devoid  of  the 
disagreeable  odor  of  the  latter,  but  it  is  not  a  harmless  remedy,  as  was 
at  first  supposed,  for  several  cases  of  bismuth  poisoning  have  been 
recorded  from  its  surgical  use.  Like  iodoform,  its  value  depends  not 
so  much  on  its  germicidal  action  as  on  its  absorption  of  the  fluids  of 
the  wound,  which  renders  the  surface  less  suitable  for  the  growth  of 
bacteria.  The  therapeutic  uses  of  the  bismuth  preparations  then  are 
largely  due  to  their  insolubility.  The  subnitrate  is  generally  used,  the 
carbonate  less  frequently,  while  the  soluble  double  citrate  is  quite 
superfluous. 

Several  new  compounds  of  bismuth  have  been  introduced  into  therapeutics 
of  late  years,  chiefly  with  the  intention  of  combining  the  astringent  prop- 
erties of  bismuth  with  the  antiseptic  action  of  benzol  preparations.  Among 


ALUMINIUM  AND  ALUM.  695 

these  may  be  mentioned  the  salicylate  (B.  P.)  and  benzoate,  which  have  been 
used  as  intestinal  antiseptics  and  astringents.  (0.2-0.3  G.  (3-5  grs. ),  in 
powder.)  Others  are  dermatol  (gallate  of  bismuth,  C6H2(OH)3COOBiO),  airol 
(bismuth  oxyiodide  gallate),  thioform  (bismuth  dithio-salicylate),  bismuth 
phenolate,  cresolate,  orphol  (/3-naphtolate),  xeroform  (tribromphenolate),  tan- 
nate,  sulphocarbolate,  dermol  (chrysophenate),  eudoxin  (tetraiodo-phenolphtalei- 
nate).  These  have  been  used  chiefly  as  cutaneous  applications  in  various 
forms  of  skin  disease,  in  which  an  astringent  and  protective  powder  is  indi- 
cated, in  burns  and  ulcers,  in  some  ophthalmic  conditions,  and  as  dusting 
powders  after  operations.  Several  of  them,  such  as  dermatol  (0.1-0.2  G.), 
and  the  phenolate,  cresolate,  naphtolate,  and  tribromphenolate  (1-4  G.), 
have  been  advised  as  intestinal  antiseptics  and  astringents,  and  the  last  four 
have  been  shown  to  be  decomposed  in  the  intestine  into  bismuth  and  the 
corresponding  aromatic  antiseptic.  Stomatitis  and  other  symptoms  have 
been  observed  occasionally  from  the  external  application  of  these  new  com- 
pounds, but  they  seem  less  dangerous  than  the  subnitrate  in  ordinary  sur- 
gical use.  Ttye  phenol,  cresol,  and  other  similar  substances  freed  by  the 
decomposition  of  these  new  compounds,  might  also  give  rise  to  symptoms  of 
poisoning,  if  large  quantities  were  rapidly  formed  in  the  intestine.  Derma- 
tol has  no  effect  on  the  double  sulphates  of  the  urine,  so  that  it  apparently 
does  not  act  as  a  germicide,  but  merely  as  an  astringent  protective  in  the 
intestine. 

BIBLIOGRAPHY. 

Meyer  u.  Stein/eld.     Arch.  f.  exp.  Path.  u.  Pharm.,  xx.,  p.  40. 

Dalcheand  Villejean.     Arch.  gen.  de  Med.,  1887,  ii.,  p.  129. 

Jasenski.     Arch,  des  Sciences  biolog.,  ii.,  p.  247. 

Surveyor  and  Harley.     Brit.  Med.  Jour.,  1895,  ii.,  p.  1483. 

Fleiner.     Centralbl.  f.  klin.  Med.,  1893,  p.  69  (supplement). 

Malthes.     Centralbl.  f.  inn.  Med.,  1894,  p.  2. 

Cramer.     Munch,  med.  Woch.,  1896,  p.  587. 

Heinz.     Berl.  klin.  Woch.,  1892,  p.  1190. 

Kocher.     Volkmann's  Klinische  Vortrage,  No.  224. 

Petersen.     Deutsch.  med.  Woch.,  1883,  p.  365. 

Savdieff.     Therapeut.  Monatsh.,  1894,  p.  485. 

Cerium. 

Cerium  is  used  to  a  limited  extent  in  therapeutics  in  the  form  of  the 
oxalate.  Very  little  is  known  of  its  effects,  but  it  is  apparently  absorbed 
with  difficulty  from  the  stomach  and  intestine.  It  is  said  to  depress  the 
heart,  and  to  induce  vomiting  and  purging,  with  hyperaBmia  and  ecchymoses 
in  the  stomach  and  bowel,  and  nephritis  and  congestion  in  the  kidney,  when 
it  is  injected  into  the  blood  vessels. 

In  therapeutics  it  is  used  in  vomiting  from  seasickness,  pregnancy  and 
other  conditions,  in  which  irritation  of  the  stomach  is  not  the  primary  cause. 
It  is  quite  unknown  how  it  acts  in  these  cases,  but  it  is  surmised  that  its  ef- 
fects are  local  and  similar  to  those  of  bismuth  subnitrate. 

Cerii  Oxalas  (U.  S.  P.,  B.  P.)  (Ce2(C2O4)3+9H2O),  a  white  granular  powder, 
tasteless,  odorless,  insoluble  in  water  or  alcohol.  0.1-0.6  G.  (2-10  grs.). 

IX.     ALUMINIUM  AND  ALUM. 

The  chief  pharmacopoeial  preparation  of  aluminium  is  the  sulphate  of 
aluminium  and  potassium,  or  alum,  which  has  been  largely  used  for  its 
astringent  properties.  Alum  solutions  precipitate  albumin,  but  the 
precipitate  is  soluble  in  excess  of  the  proteid.  It  is  not  known 
whether  an  albuminate  is  formed  similar  to  those  of  the  heavy  metals, 
though  it  seems  probable  that  this  is  the  case.  Dilute  solutions  of  alum 


696  THE  HEAVY  METALS. 

have  an  astringent  effect  from  their  throwing  down  a  layer  of  precip- 
itated proteid  on  the  surface  of  the  mucous  membranes  or  on  wounded 
surfaces,  but  larger  quantities  and  more  concentrated  solutions  act  as 
irritants.  This  is  more  especially  the  case  when  dried  alum  is  applied, 
for,  in  addition  to  its  coagulating  effect  on  the  proteids,  this  prepara- 
tion has  a  great  avidity  for  water. 

Symptoms.  —  Alum  solutions  have  a  sweetish,  astringent  taste,  and  in 
small  quantities  induce  no  symptoms  except  a  feeling  of  dryness  and 
astringency  of  the  mouth  and  throat,  and  some  constipation.  Larger 
doses  act  as  gastric  irritants  and  cause  nausea  and  vomiting,  and,  in 
extreme  cases,  purging.  Even  the  largest  quantities,  however,  are 
followed  by  no  symptoms  except  those  of  gastro-intestinal  irritation 
and  inflammation,  and  the  long-continued  use  of  alum  does  not  elicit 
any  symptoms  of  chronic  poisoning.  The  aluminium  salts  are  not  ab- 
sorbed in  any  quantity  from  the  stomach  and  intestine,  so  that  no 
symptoms  of  general  poisoning  arise  from  the  internal  use  of  the  salt. 
Aluminium  vessels  may  be  used  for  cooking,  or  even  to  contain  acids, 
without  danger  of  intoxication,  as  has  been  shown  by  a  recent  series 
of  investigations. 

Aluminium  salts,  especially  the  acetate,  chloride  and  some  more 
recent  preparations,  have  very  considerable  antiseptic  power,  much 
more  than  some  of  the  more  generally  used  antiseptics,  such  as  boric 
acid. 

Action.  —  Aluminium  has  a  very  remarkable  general  action  when  it 
obtains  access  to  the  blood.  In  Siem's  experiments  on  animals,  the  sodium- 
aluminium  lactate  or  tartrate  induced  a  very  slow  intoxication,  mammals 
never  dying  from  the  effects  sooner  than  one  or  two  weeks  after  the  in- 
travenous injection  of  the  salts.  In  frogs  the  symptoms  were  those  of  a  de- 
scending paralysis  of  the  central  nervous  system,  the  heart  and  the  peripheral 
nerves  and  muscles  being  little  affected.  In  mammals  the  first  symptoms 
appeared  only  after  three  to  five  days,  and  consisted  in  constipation,  rapid 
loss  of  weight,  weakness,  torpor  and  vomiting  ;  marked  abnormalities  in 
movement  and  sensation  were  observed  later,  such  as  tremor,  jerking 
movements,  clonic  convulsions,  paresis  of  the  hind  legs,  anaesthesia  of  the 
mouth  and  throat,  and  lessened  sensation  all  over  the  body.  Before 
death,  diarrhoea  often  set  in,  and  albuminuria  was  generally  present. 
The  mucous  membrane  of  the  stomach  and  bowel  was  found  swollen  and 
congested,  the  kidney  and  liver  had  often  undergone  fatty  degeneration, 
and  haemorrhages  were  found  in  the  renal  cortex.  Aluminium  was  found  in 
the  urine. 

Like  the  other  members  of  the  heavy  metal  series,  aluminium  therefore 
acts  on  the  bowel  and  kidney  in  general  poisoning,  while  many  of  the  symp- 
toms point  to  a  direct  action  on  the  brain.  Dollken  has  recently  confirmed 
Siem's  results,  and  showed  that  the  nerve  cells  and  fibres  of  the  cord  and 
medulla  undergo  degeneration,  particularly  those  of  the  lower  cranial  nerves. 

It  has  been  stated  that  the  alum  salts  of  the  food  are  absorbed  and  stored 
in  the  bones,  but  this  is  incorrect.  What  little  is  absorbed  is  probably  rap- 
idly excreted  by  the  bowel  and  perhaps  by  the  urine. 

A  metal  which  is  very  nearly  related  to  aluminium  in  its  effects  in  the 
organism  is  Beryllium.  It  differs  chiefly  in  being  more  poisonous,  in  being 
absorbed  from  the  stomach  and  intestine,  and  in  causing  more  distinct  lesions 
in  these  when  it  is  injected  into  the  blood. 


ALUMINIUM  AND  ALUM.  697 


PREPARATIONS. 

ALUMEN  (U.  S.  P.,  B.  P.),  alum,  potassium  alum,  (A12K2(SO4)4  +  24H2O), 
large,  colorless,  octahedral  crystals,  with  a  sweetish,  strongly  astringent 
taste,  soluble  in  water,  but  not  in  alcohol.  0.3-1  G.  (5-15  grs.). 

Glycerinum  Aluminis  (B.  P.),  10  per  cent. 

Alumen  Exsiccatum  (U.  S.  P.),  Alumen  Ustum  (B.  P.),  burnt  alum,  dried 
alum  (A12K2(SO4)4),  a  white,  granular  powder,  attracting  moisture  on  ex- 
posure to  air,  soluble  in  water. 

Alumini  Rydroxidum  (U '.  S.  P.)  (A12(OH)6),  a  white,  light,  amorphous  powder, 
odorless,  tasteless,  insoluble  in  water  or  alcohol,  but  soluble  in  hydrochloric 
or  sulphuric  acid  and  in  fixed  alkalies.  0.3-1  G.  (5-15  grs.). 

Alumini  Sulphas  (U.  S.  P.)  (A12(SO4)3),  a  white,  crystalline  powder,  with  a 
sweetish,  astringent  taste,  soluble  in  water,  not  in  alcohol. 

Uses.  —  Alum  is  used  chiefly  externally  for  its  astringent  properties. 
It  has  been  employed  as  an  emetic,  but  is  less  reliable  than  the  sul- 
phate of  copper  or  tartar  emetic,  and  very  large  doses  (4-8  G.,  1-2 
drs.)  are  required.  In  diarrhoaa  either  alum  or  the  hydrate  is  some- 
times advised. 

Alum  solution  is  useful  as  an  astringent  gargle  (1-5  per  cent.),  as 
an  injection  in  gonorrhoea  (J-l  per  cent.),  as  an  astringent  lotion  in 
skin  diseases  (1  per  cent.),  and  for  other  similar  purposes.  It  is  said 
to  tend  to  cause  corneal  perforation  by  dissolving  the  intercellular  sub- 
stance, but  has  been  used  in  ophthalmia  by  many  surgeons.  Dried 
alum  is  more  caustic,  from  its  withdrawing  fluid  from  the  tissues.  It 
has  been  used  to  a  limited  extent  as  an  emetic ;  more  frequently  as  an 
application  to  exuberant  granulations,  haemorrhoids,  or  condylomata, 
and  as  a  styptic  in  bleeding  from  the  nose  or  teeth.  Alum  has  often 
been  prescribed  in  chronic  lead  poisoning  with  success.  A  one  per 
cent,  solution  has  been  injected  into  the  rectum  in  chronic  dysentery, 
but  is  inferior  to  the  nitrate  of  silver. 

A  large  number  of  aluminium  preparations  have  been  introduced  recently 
as  antiseptic  astringents.  Among  these  may  be  mentioned  alumnol  (naph- 
tol  sulphonate  of  aluminium),  salumin  (salicylate),  tannal  (tannate),  gallal 
(gallate),  boral  (borotartrate),  cutol  (borotannate),  alsol  (acetate),  alkasal 
(salicylate  of  potassium  and  aluminium).  They  are  used  partly  in  solution, 
chiefly  as  dusting  powders,  but  it  has  yet  to  be  proved  that  they  are  supe- 
rior to  the  older  preparations.  As  with  so  many  of  the  products  of  the  new 
industrial  chemistry,  they  are  thrown  on  the  market  in  such  profusion,  and 
are  heralded  with  such  exaggerated  praise,  that  it  is  impossible  at  present  to 
state  which  of  them  are  really  improvements  on  the  more  generally  recog- 
nized preparations,  and  which  are  merely  adapted  to  enrich  the  inventor, 
without  materially  advancing  therapeutics. 

BIBLIOGRAPHY. 

Stem.     Inaug.  Diss.,  Dorpat,  1886. 
DoUIcen.     Arch.  f.  exp.  Path.  u.  Pharm.,  xl.,  p.  98. 
Jalandela  Oroix.     Ibid.,  xiii.,  p.  210. 
Heinz.     Berl.  klin.  Woch.,  1892,  p.  1158.     (Alumnol.) 

Plagge  u.  Lebbin.  Ueber  Feldflaschen  und  Kochgeschirre  aus  Aluminum,  Berlin, 
1893. 


698  THE  HEAVY  METALS. 

X.    MINOR  METALS. 

Gold. 

Gold  has  never  been  largely  used  in  therapeutics,  although  repeated  at- 
tempts have  been  made  to  introduce  it  in  the  treatment  of  the  most  diverse 
conditions  ;  the  salt  employed  has  almost  invariably  been  the  double  chlor- 
ide of  gold  and  sodium.  It  is  much  less  poisonous  than  many  of  the  other 
metals  and  may  be  taken  for  many  months  without  entailing  any  untoward 
symptoms.  The  subcutaneous  injection  in  frogs  is  followed  by  paralysis  of 
the  central  nervous  system,  gold  possessing  little  action  on  the  heart  and 
striated  muscles  in  these  animals.  Injected  intravenously  in  dogs,  it  causes 
vomiting  and  dyspnoea,  which  soon  pass  off,  but  if  sufficient  has  been  in- 
jected the  animal  suffers  from  nausea,  vomiting  and  diarrhoea  for  several 
days,  eats  nothing,  loses  flesh  rapidly,  and  dies  a  week  or  more  after  the  ex- 
periment. Numerous  ulcers  are  found  in  the  stomach  and  intestine,  and 
these  often  betray  their  presence  in  life  by  haemorrhages.  Gold  lowers  the 
blood  pressure  somewhat  on  intravenous  injection,  probably  from  the  dila- 
tion of  the  mesenteric  vessels  accompanying  the  intestinal  action.  It  has 
little  effect  on  the  rate  of  the  heart  except  in  large  doses,  and  dilates  the 
vessels  when  perfused  through  them.  When  given  by  the  mouth  to  dogs 
and  cats,  it  is  at  once  ejected  from  the  stomach  by  vomiting. 

Gold  has  therefore  the  ordinary  general  effects  of  the  heavy  metals  in 
causing  acute  irritation  and  ulceration  of  the  alimentary  canal.  The  early 
vomiting  may  be  due  to  action  on  the  centre,  but  is  more  probably  caused 
by  its  irritating  the  stomach.  The  diarrhoea,  and  the  ulceration  of  the 
stomach  and  intestine  probably  indicate  that  it  is  excreted  by  these  organs. 

Auri  et  Sodii  Chloridum  (U.  S.  P.),  a  mixture  of  equal  parts  by  weight  of 
dry  gold  chloride  (AuCl3)  and  sodium  chloride  (NaCl),  an  orange-yellow 
powder,  with  a  saline,  metallic  taste,  deliquescent  in  the  air  and  very  solu- 
ble in  water.  0.005-0.03  G.  (jV-£  gr-)>  in  solution.  Gold  has  been  used  in 
various  nervous  disorders,  in  particular  in  those  of  a  hysterical  nature,  and 
may  conceivably  be  of  value  through  suggestion,  if  the  patient  be  informed 
of  the  nature  of  the  remedy.  It  has  also  been  advised  in  syphilis,  rheuma- 
tism, and  other  chronic  diseases.  Of  late  years  it  has  been  widely  adver- 
tised as  a  specific  in  chronic  alcoholism,  but  analysis  has  shown  that  no  gold 
was  contained  in  the  fluid  advocated,  and  there  is  no  reason  to  suppose  that 
it  is  of  value  except  by  means  of  suggestion.  Kantnack  and  Calmette  have 
recommended  its  hypodermic  injection  in  cases  of  snake  bite. 

BIBLIOGRAPHY. 

Aronowitsch.     Inaug.  Dissertation,  Wurzburg,  1881. 
Schultz.     Inaug.  Dissertation,  Dorpat,  1892. 

Platinum. 

Platinum  resembles  gold  in  its  action  very  closely,  but  is  much  more  poi- 
sonous. In  the  frog  it  paralyzes  the  central  nervous  system,  and  later  the 
striated  muscles.  Kebler  observed  a  stage  of  convulsions  precede  that  of 
paralysis,  the  spasms  evidently  arising  from  the  spinal  cord  or  medulla 
oblongata.  In  mammals  the  symptoms  resemble  those  of  gold  poisoning  in 
almost  every  detail.  Small  quantities  of  platinum  double  salts  injected  in- 
travenously increase  the  urine  to  some  extent ;  larger  injections  cause  albu- 
minuria. 

Platinum  was  at  one  time  advised  in  syphilis,  but  has  never  been  widely 
used. 

BIBLIOGRAPHY. 

Kebler.     Arch.  f.  exp.  Path.  u.  Pharra.,  ix.,  p.  137. 
Cohnstein.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxx.,  p.  127. 


CHROMIUM.  699 

Chromium. 

Chromium  is  used  in  medicine  in  the  form  of  chromic  acid  and  the  bichro- 
mate of  potassium,  which  are  both  powerful  oxidizing  bodies  in  addition  to 
their  poisonous  action  as  metallic  oxides,  fhe  former  property  renders 
them  more  irritant  and  corrosive  than  most  of  the  salts  of  the  heavy  metals. 
Chromic  acid  in  particular  is  a  powerful  caustic,  combining  the  action  of  a 
metallic  oxide,  an  acid,  and  a  strongly  oxidizing  agent.  Applied  to  the  skin 
in  substance  it  corrodes  it,  but  is  said  to  cause  less  pain  than  the  more  pene- 
trating caustic  potash.  Even  in  dilute  solution  the  chromic  salts  and  the 
acid  act  as  skin  irritants,  and  the  caustic  effects  are  shown  by  skin  diseases, 
and  particularly  by  deep  perforating  ulcers  in  persons  exposed  constantly  to 
the  dust  of  chromic  salts  in  factories.  These  ulcers  arise  from  any  abrasion 
of  the  skin,  while  the  acid  does  not  seem  to  be  capable  of  penetrating  the 
unbroken  epidermis.  The  cartilaginous  septum  of  the  nose  is  also  a  common 
seat  of  ulceration,  which  eventually  leads  to  perforation.  These  ulcers  arise 
from  the  local  action  of  the  poison  and  not  from  its  absorption  ;  they  are  said 
to  be  almost  painless.  The  inhalation  of  the  dust  leads  to  chronic  bronchitis, 
while  that  swallowed  and  absorbed  may  give  rise  to  nephritis. 

Symptoms. — In  acute  poisoning,  when  a  large  quantity  of  the  acid  or  of  a 
salt  is  swallowed,  the  symptoms  are  those  of  gastro-intestinal  corrosion,  in- 
tense pain  in  the  throat  and  stomach,  vomiting  and  purging,  with  blood  in  the 
vomited  matter  and  the  stools,  collapse  and  frequently  death.  The  mouth 
and  throat  are  stained  yellow,  and  the  stomach  and  intestine  exhibit  the 
usual  appearance  of  violent  corrosive  poisoning. 

The  general  action  of  chromic  preparations  may  be  elicited  in  animals  by 
subcutaneous  or  intravenous  injection,  or  by  the  administration  of  smaller 
quantities  by  the  mouth.  The  symptoms  resemble  those  caused  by  the  gen- 
eral action  of  other  metals.  In  the  frog  increasing  weakness,  tremor  and 
eventually  paralysis  of  the  central  nervous  system  are  induced.  In  the 
mammal  weakness  and  slowness  in  the  movements  is  followed  by  albumi- 
nuria,  glycosuria,  diarrhoea  and  vomiting.  Sometimes  twitching  of  the 
muscles  or  even  convulsions  are  seen,  and  then  the  weakness  passes  into 
general  paralysis.  The  heart  seems  little  affected  by  chromium,  but  the 
blood-pressure  falls.  After  death  the  stomach  and  bowel  are  found  con- 
gested, and  the  mucous  membrane  is  necrosed  and  ulcerated  in  some  parts, 
covered  with  ecchymoses  in  others.  Hemorrhages  are  also  found  in  other 
organs  of  the  body,  notably  in  the  heart  wall.  The  kidney  is  in  a  state  of 
acute  parenchymatous  nephritis  and  often  contains  deposits  of  uric  acid,  and 
albumin,  casts,  and  often  blood  cells  appear  in  the  urine.  In  chronic  poison- 
ing interstitial  nephritis  is  said  to  occur. 

Chromic  acid  and  its  salts  are  readily  absorbed  from  the  stomach  and  in- 
testine. They  seem  to  be  excreted  for  the  most  part  through  the  kidney,  to 
a  less  extent  by  the  intestinal  epithelium  probably.  In  the  urine  the  metal 
occurs  in  part  in  organic  combinations. 

Chromic  oxide  compounds  act  in  the  same  way  as  the  chromates,  but  are 
much  less  poisonous. 

PREPARATIONS. 

Acidum  Chromicum  (B.  P.),  Chromii  Trioxidum  (U.  8.  P.),  chromic  acid  or 
anhydride  (CrO3),  forms  crystals  of  dark  purplish-red  color  and  metallic  lustre, 
odorless,  very  soluble  in  water.  When  brought  in  contact  with  organic  sub- 
stances, such  as  alcohol,  glycerin  or  sugar,  it  oxidizes  them  rapidly  and  often 
violently  with  explosion. 

Liquor  Acidi  Chromici  (B.  P.),  25  per  cent. 

Potassii  Bichromas  (B.  P.),  Potassii  Dichromas  (U.  S.  P.),  bichromate  or 
dichromate  of  potassium  (K2Cr2O7),  forms  large,  orange-red  transparent  crystals, 
with  a  bitter  metallic  taste,  soluble  in  ten  parts  of  water.  6-12  mgs.  (TV-£  gr. ). 

Chromic    acid    is    used    as    a    caustic    application   to   malignant   growths, 


700  THE  HEAVY  METALS. 

chancres  and  diphtheritic  membranes,  to  a  less  extent  as  an  irritant  antisep- 
tic. It  has  generally  been  applied  by  dipping  a  glass  rod  into  a  solution 
formed  by  allowing  the  crystals  to  deliquesce,  or  it  may  be  fused  on  the  end 
of  a  wire.  It  has  also  been  advised  in  5  per  cent,  solution  as  an  application 
to  prevent  perspiration  of  the  feet  and  to  harden  the  skin. 

The  bichromate  has  been  recommended  recently  in  certain  forms  of  dys- 
pepsia in  doses  of  5  mgs.  (TV  gr.)« 

BIBLIOGRAPHY. 

Priestley.     Jour,  of  Anat.  and  Phys.,  xi.,  p.  285. 
Gergens.     Arch.  f.  exp.  Path.  u.  Pharm.,  vi.,  p.  148. 
Pander.     Robert's  Arb.  a.  d.  pharm.  Instit.  zu  Dorpat,  ii.,  p.  1. 
Hermanni.     Munch,  med.  Wochenschr.,  1901,  L,  p.  536. 
Kossa.     Pfliiger's  Arch.,  Ixxxviii.,  p.  627. 

Manganese. 

Traces  of  manganese  are  found  in  the  blood  and  tissues  of  man  and  ani- 
mals very  frequently,  but  this  metal  is  not  an  essential  constituent  of  the 
body,  but  is  apparently  absorbed  accidentally  with  the  food.  The  salts  of 
manganese  in  large  quantities  cause  acute  irritation  of  the  stomach  and  in- 
testine, like  those  of  the  other  heavy  metals,  but  no  symptoms  pointing  to 
effects  from  the  absorption  of  the  metal  are  observed  even  when  the  adminis- 
tration is  continued  for  a  long  time.1  Manganese  is  absorbed  from  the  ali- 
mentary tract,  however,  but  only  in  very  small  quantity,  and  it  appears  to 
resemble  iron  closely  in  its  course  through  the  tissues  (see  page  664).  Its 
general  action  has  been  elicited  by  the  hypodermic  or  intravenous  injection 
of  double  salts.  In  frogs  manganese  injected  hypodermically  causes  a  de- 
scending paralysis  of  the  brain  and  spinal  cord,  and  later  weakens  and 
arrests  the  heart,  while  the  peripheral  muscles  and  nerves  seem  unaffected. 
In  mammals  large  injections  induce  epileptiform  convulsions,  particularly  in 
the  rabbit  and  guinea-pig.  Smaller  quantities,  which  cause  a  less  acute  intoxi- 
cation, induce  in  the  dog,  nausea  and  vomiting,  diarrhoea,  weakness,  som- 
nolence, stupor  and  death  from  arrest  of  the  respiration.  The  urine  is  often 
increased,  and  contains  bile  pigment,  and,  towards  death,  albumin  and 
casts.  The  stomach  and  bowel  present  no  congestion  or  ulceration  in  these 
cases.  Manganese  is  found  in  the  vomited  matter  and  the  stools,  in  the 
liver,  kidney  and  intestinal  wall,  to  a  less  extent  in  the  other  organs.  In 
acute  poisoning  in  mammals  the  blood-pressure  falls,  from  depression  and 
paralysis  of  the  vaso-motor  centre,  while  the  heart  is  affected  only  much 
later.  In  subacute  poisoning  the  darker  color  of  the  urine  indicates  icterus, 
but  this  is  much  more  marked  when  small  quantities  are  repeatedly  injected 
into  the  subcutaneous  tissues,  and  chronic  poisoning  induced.  In  chronic 
cases  the  nephritis,  which  is  shown  in  acute  poisoning  by  albuminuria,  is 
also  more  developed,  the  inflammation  commencing  in  the  secretory  cells  of 
the  kidney  but  later  involving  the  interstitial  tissue,  if  the  animal  lives  long 
enough. 

Manganese  injected  hypodermically  or  subcutaneously,  is  excreted  chiefly 
by  the  intestinal  epithelium,  to  a  less  extent  by  the  kidney. 

PREPARATIONS. 

Mangani  Dioxidum  Prcecipitatum  (U.  S.  P.).     Dose,  0.25  G.  (4  grs.). 

Mangani  Sulphas  (U.  S.  P.)  (MnSO4  +  4H2O),  colorless,  or  pale  rose-colored 
crystals  with  a  somewhat  bitter,  astringent  taste,  soluble  in  water,  not  in  alcohol. 
0.1-0.5G.  (2-8  grs.). 

Mangani  Hypophosphis  (U.  S.  P.)  (Mn(PH2O2)2).      0.2  G.  (3  grs.). 

1  Symptoms  ascribed  to  chronic  poisoning  have  recently  been  described  by  Embden 
as  occurring  in  workmen  in  manganese. 


MANGANESE.  701 

Manganese  has  been  advised  in  chlorosis  and  especially  in  amenorrhoea, 
in  which  it  is  believed  by  many  to  have  a  specific  action,  while  others  have 
found  it  of  no  value  in  either  of  these  conditions.  In  amenorrhcea  the  per- 
manganate of  potassium  is  generally  prescribed  instead  of  the  dioxide  or  sul- 
phate, but  as  it  is  at  once  reduced  in  the  stomach,  the  effect  is  the  same  as 
if  pure  dioxide  was  administered. 

BIBLIOGRAPHY. 

Harnack.     Arch.  f.  exp.  Path.  u.  Pharm.,  iii.,  p.  58  ;  xlvi.,  p.  372. 

Robert.     Ibid.,  xvi.,  p.  361. 

Cahn.     Ibid.,  xviii.,  p.  129. 

Stockman.     Brit.  Med.  Jour.,  1893,  i.,  p.  942. 

Embden.     Deutsch.  med.  Woch.,  1901,  p.  795. 

Cadmium  resembles  zinc  very  closely  in  its  effects. 

Nickel  and  Cobalt  salts,  administered  to  the  frog,  cause  a  curious  dark 
color  in  the  skin,  followed  by  convulsive  movements,  which  at  first  arise  ap- 
parently from  the  medulla  oblongata  and  higher  centres,  and  resemble  those 
of  picrotoxin,  but  later  are  reflex  from  excessive  irritability  of  the  spinal 
cord.  In  mammals  the  usual  symptoms  arising  from  the  action  on  the  in- 
testine and  kidney  are  accompanied  by  tremors  and  chorea-like  movements, 
later  by  tetanus,  and  finally  by  paralysis.  Strongly  acid  food  may  form 
nickel  salts  when  it  is  cooked  in  vessels  made  of  this  metal,  but  no  poison- 
ing results,  either  because  the  quantity  ingested  is  too  small  or  because  it  is 
slowly  absorbed  from  the  stomach  and  intestine.  Cobalt  nitrate  has  been 
recommended  as  an  antidote  in  prussic  acid  poisoning,  as  it  forms  an  insoluble 
cyanide,  but  appears  to  be  of  little  or  no  value  ;  the  oxide  has  been  applied 
externally  as  an  astringent,  antiseptic  powder. 

Tin  salts  paralyze  the  central  nervous  system  in  the  frog,  and  later  the 
heart.  In  mammals,  diarrhoea,  colic,  vomiting  and  general  weakness  are 
observed,  along  with  paralysis  of  some  parts  of  the  central  nervous  system 
and  stimulation  of  others,  leading  to  ataxia,  stiffness  and  irregularity  of  the 
movements,  and  occasionally  convulsions.  The  sulphide  is  said  to  be  de- 
posited in  the  lymph  spaces  of  the  intestines  in  the  same  way  as  in  bismuth 
poisoning.  General  poisoning  may  be  induced  by  the  administration  of  the 
salts  by  the  mouth,  even  when  there  is  no  corrosion  of  the  mucous  mem- 
brane. Tin  is  often  contained  in  preserved  foods  containing  acids  from  being 
dissolved  off  the  vessels,  and  is  certainly  absorbed,  for  it  has  been  detected  in  the 
urine  after  the  use  of  such  articles.  Apparently  it  is  not  often  present  in  sufficient 
quantities  to  induce  poisoning,  for  although  some  cases  of  ' '  tin  poisoning ' '  are 
met  with  in  medical  literature,  in  none  of  them  has  it  been  satisfactorily  estab- 
lished that  tin  was  the  cause.  Chronic  poisoning  from  this  cause  is  unknown, 
and  animals  present  no  symptoms  from  prolonged  treatment  with  larger  quanti- 
ties of  tin  than  are  contained  in  any  preserved  foods  (Lehmann). 

Thallium  salts  seem  to  resemble  those  of  lead  in  their  effects,  but  have  a 
powerful  depressant  action  on  the  heart,  and  are  said  to  be  more  poisonous. 
Richet  states  that  the  injection  of  thallium  acetate  in  animals  is  followed  by  a 
general  atrophy  of  the  muscles,  especially  of  those  of  the  jaw  and  spine,  while 
baldness  has  followed  its  continual  use  in  man. 

Vanadium  presents  only  the  ordinary  characteristics  of  metallic  poison- 
ing. The  different  oxides  vary  in  toxicity,  the  pyrovanadates  being  much 
the  most  powerful. 

Molybdenum  and  Tungsten  resemble  each  other  closely,  and  induce 
typical  metallic  poisoning. 

Uranium,  in  addition  to  the  ordinary  features  of  metallic  intoxication, 
causes  some  glycosuria,  the  sugar  often  amounting  to  one  per  cent,  in  the 
urine.  This  may  probably  be  explained  by  the  recently  discovered  fact  that 
this  metal  retards  the  reduction  of  the  oxyhsemoglobin  of  the  blood,  for 


702  THE  HEAVY  METALS. 

lessened  oxidation  in  the  tissues  has  been  shown  to  cause  some  glycosuria  in 
a  number  of  instances. 

Selenium  and  Tellurium  are  classed  along  with  sulphur  in  chemical  sys- 
tems, but  the  salts  of  telluric,  selenious  and  selenic  acid  induce  symptoms 
resembling  those  of  the  heavy  metals  and  arsenic  in  many  points,  and  may 
be  inserted  in  this  series.  In  the  frog  the  symptoms  are  those  of  central 
nervous  paralysis,  and  later  of  heart  failure.  In  mammals  vomiting,  purg- 
ing, somnolence,  dyspnoea,  tonic  and  clonic  convulsions  have  been  noted, 
and  the  stomach  is  found  somewhat  reddened,  the  mucous  membrane  of  the 
intestine  swollen  and  dysenteric,  while  the  kidneys  seem  less  affected.  The 
perspiration  is  prevented  by  tellurates,  apparently  from  a  paralysis  of  the 
terminations  of  the  secretory  nerves  similar  to  that  induced  by  atropine. 
An  early  symptom  of  poisoning  with  these  bodies  is  a  garlic  odor  in  the 
breath,  and  many  of  the  organs  are  found  of  a  grayish  color  after  death,  and 
possess  this  odor.  Hofmeister  has  shown  that  these  salts  are  reduced  to 
metallic  selenium  and  tellurium  in  the  body,  and  that  afterwards  methyl 
compounds  (Te(CH3)2,  Se(CH3)2)  are  formed.  These  are  volatile,  and,  ex- 
creted by  the  lungs,  urine  and  faeces,  give  the  disagreeable  odor.  The  syn- 
thesis of  methyl -tellurium  is  one  of  the  few  known  cases  in  which  a  com- 
pound with  methyl  is  formed  in  the  animal  body,  and  is  of  great  biological 
importance.  All  the  selenium  and  tellurium  is  not  excreted  in  this  form,  for 
some  of  it  appears  in  the  urine,  and  probably  in  the  fasces,  in  other  combina- 
tions. 

Tellurates  have  been  advised  in  therapeutics  to  prevent  excessive  sweat- 
ing, and  certainly  have  tjiis  effect,  but  are  not  to  be  recommended,  as  the 
strong  garlic  odor  of  the  breath  persists  for  days  or  even  weeks  after  one 
dose. 

Osmic  Acid  has  been  recommended  as  an  injection  into  the  nerves  in 
neuralgia.  It  is  an  intensely  irritant  substance,  and  seems  to  induce  ne- 
phritis and  diarrhoaa  when  absorbed.  The  greater  part  of  the  poison  is,  how- 
ever, deposited  as  a  black  powder  at  the  point  of  injection,  owing  to  its 
being  reduced  by  the  tissues. 

BIBLIOGRAPHY. 
Cadmium. 

Marme.     Ztschr.  f.  rat.  Med.,  xxix.,  p.  125. 

Wheeler.     Boston  Med.  and  Surg.  Journ.,  xcv.,  p.  434. 

Nickel  and  Cobalt. 

Stuart.     Journ.  of  Anat.  and  Phys.,  xvii.,  p.  89.     Arch.  f.  exp.  Path.  u.  Pharm. 
xviii.,  p.  151. 

Rohde.     Arch.  f.  Hygiene,  ix.,  p.  331. 

Hiibner.     Arch,  internat.  de  Pharmacodyn. ,  ix.,  p.  339. 

Tin. 

White.     Arch.  f.  exp.  Path.  u.  Pharm.,  xiii.,  p.  53. 
Lehmann.     Arch.  f.  Hygiene,  xlv.,  p.  88. 

Thallium. 

Luck.     Inaug.  Diss.,  Dorpat,  1891. 
Eichet.     Comptes  rend,  de  la  Soc.  de  Biol.,  1899,  252. 
Bullard.     Boston  Med.  and  Surg.  Journ.,  1902  (2),  p.  589. 
Luzzato.     Biochem.  Centralbl.,  ii.,  p.  86. 

Vanadium. 

Priestley.     Phil.  Trans,  of  Koy.  Soc.,  clxvi.,  p.  495. 

Gamgee  and  Larmuth.     Journ.  of  Anat.  and  Phys.,  xi.,  pp.  235,  251. 

Dowdeswell.     Jour,  of  Phys.,  i.,  p.  257. 

Tungsten. 

Bemstein-Kohan.     Robert's  Arbeit,  a.  d.  pharm.  Instit.  zu  Dorpat,  v.,  p.  42. 


MINOR  METALS.  703 

Uranium. 

Worosckihky.     Robert's  Arbeit,  a.  d.  pharm.  Instit.  zu  Dorpat,  v.,  p.  1. 

Chittenden.     Studies  from  the  Lab.  of  Phys.  Chem.  of  Sheffield  Scientific  School,  i., 
ii.,  iii. 

Selenium  and  Tellurium. 

Czapek  u.  Weil.     Arch.  f.  exp.  Path.  u.  Pharm.,  xxxii.,  p.  438. 
Hofvneister.     Ibid.,  xxxiii.,  p.  198. 

Gies  and  Mead.     Amer.  Journ.  of  Phys.,  v.,  p.  104 ;  Philadelphia  Med.  Journ., 
1901,  p.  566. 


PART  V. 

FERMENTS,  SECRETIONS  AND  TOXALBUMINS. 

I.    DIGESTIVE  FERMENTS. 

A  NUMBER  of  digestive  ferments  have  been  introduced  into  thera- 
peutics for  the  treatment  of  gastric  and  intestinal  disorders.  The 
earlier  members  of  the  series  were  proteolytic  ferments,  intended  to 
reinforce  the  pepsin  of  the  stomach,  but  of  recent  years  the  amylolytic 
ferments  have  also  been  strongly  advocated. 

Pepsin. 

The  pharmacopeia!  preparations  of  pepsin  are  generally  obtained 
from  the  pig's  stomach.  Their  origin  is  not  a  matter  of  indifference, 
for  it  has  been  recently  shown  that  pepsins  obtained  from  different 
species  of  animals  differ  considerably  in  their  behavior  towards  vari- 
ous acids.  Pepsin  digests  only  in  acid  solution,  the  best  results  being 
obtained  in  a  solution  of  0.2  per  cent,  of  hydrochloric  acid.  (See  Acids, 
page  561.)  In  alkaline  solution  it  is  inert,  and  in  fact  is  rapidly  de- 
composed, so  that  when  pepsin  and  alkaline  carbonates  or  bicarbonates 
are  prescribed  together,  the  effects  are  due  to  the  alkalies  only. 

Pepsin  is  used  in  therapeutics  on  the  theory  that  the  stomach  does 
not  secrete  enough  of  the  ferment  in  certain  conditions.  But  it  may 
be  questioned  whether  this  is  true  in  even  a  small  proportion  of  the 
cases  treated  with  pepsin,  for  the  gastric  juice  is  almost  always  capable 
of  digesting  proteids  if  it  is  acid  in  reaction.  In  a  number  of  forms 
of  dyspepsia  the  acid  secretion  is  insufficient,  but  the  ferment  is  almost 
always  present  in  quantity,  for  it  digests  proteids  outside  the  body  as 
soon  as  it  is  acidulated.  Pepsin  is  indicated  then  only  in  the  rare 
cases  in  which  the  contents  of  the  stomach  acidulated  with  hydro- 
chloric acid  fail  to  digest  proteids.  It  is  very  often  administered  in 
other  forms  of  dyspepsia,  and  certainly  does  no  harm,  but  there  is  no 
question  that  it  is  entirely  unnecessary  in  the  great  majority  of  the 
cases  in  which  it  is  prescribed. 

PREPARATIONS. 

Pepsinum  (U.  S.  P.,  B.  P.),  a  proteolytic  ferment  obtained  from  the  glan- 
dular layer  of  fresh  stomachs  from  healthy  pigs,  and  capable  of  digesting 
not  less  than  3,000  times  its  own  weight  of  freshly  coagulated  egg  albu- 
min.1 It  is  a  fine,  white,  amorphous  powder  or  thin  scales,  free  from 

1  The  B.  P.  preparation  may  be  obtained  from  the  pig,  sheep  or  calf  and  is  required 
to  digest  2,500  times  its  weight  of  hard-boiled  white  of  egg. 

45  705 


706  FERMENTS,  SECRETIONS  AND  TOXALBUM1NS. 

offensive  odor  and  having  a  mildly  acid  or  saline  taste,  usually  followed  by 
a  suggestion  of  bitterness.  It  is  soluble  in  about  100  parts  of  water,  but  is 
more  soluble  if  the  water  is  acidulated.  0.3-0.6  G.  (5-10  grs.),  in  powder, 
or  in  solution  in  0.2  per  cent,  hydrochloric  acid. 

Pepsin  is  generally  given  during  or  after  meals.  As  has  been  stated,  it  is 
very  rarely  indicated,  as  the  gastric  juice  almost  always  contains  sufficient 
ferment. 

Ghjcerinwn  Pepsini  (B.  P.)  contains  hydrochloric  acid.  A  fluid  drachm 
represents  5  grs.  of  pepsin.  1—2  fl.  drs. 

Many  other  preparations  of  pepsin  are  used  in  popular  medicine,  to  a  less 
extent  by  the  profession.  Pepsin  wines,  for  example,  are  often  taken  as 
tonics  and  digestives,  but  the  wine  is  probably  of  greater  efficacy  than  the 
ferment.  In  these  pepsin  wines  the  ferment  is  not  destroyed,  however,  as  is 
sometimes  stated,  for  pepsin  is  able  to  digest  proteids  in  much  stronger  alco- 
holic solutions  than  they  represent. 

Pancreatic  Ferments. 

The  pancreatic  ferments  have  also  been  introduced  into  therapeutics, 
generally  in  the  form  of  an  extract  of  the  gland,  pancreatin.  These 
ferments  differ  from  pepsin  in  acting  only  in  alkaline  or  neutral  solu- 
tion, and  besides  digesting  proteids,  form  sugar  from  starch  and  sa- 
ponify and  emulsify  fats.  The  pancreatic  ferments  are  rendered  inert 
by  a  comparatively  short  exposure  to  the  acid  gastric  juice. 

The  value  of  pancreatin  is  even  more  problematical  than  that  of 
pepsin,  for  though  it  would  no  doubt  be  valuable  where  the  digestive 
ferments,  particularly  those  of  the  pancreas,  were  deficient,  this  has 
not  been  shown  to  occur.  On  the  other  hand,  the  pancreatic  ferments 
are  certainly  destroyed  in  passing  through  the  stomach.  It  has  been 
suggested,  however,  that  they  may  act  in  the  stomach,  if  they  are 
given  before  or  with  the  food,  as  the  acid  gastric  juice  is  only  secreted 
slowly,  and  some  time  must  elapse  before  the  pancreatin  is  rendered 
inert.  In  cases  in  which  there  is  a  deficiency  in  the  acid  of  the  gas- 
tric juice,  the  pancreatin  might  conceivably  act  throughout  the  stay  of 
the  food  in  the  stomach.  Attempts  have  been  made  to  preserve  the 
pancreatin  from  the  deleterious  effects  of  the  gastric  juice  by  adminis- 
tering it  in  capsules  which  are  dissolved  only  in  the  intestine.  It  is 
certainly  possible  that  the  pancreatin  may  be  useful  in  certain  cases,' 
where  the  ferments  of  the  pancreas  are  absent  and  the  acid  of  the 
stomach  so  deficient  as  not  to  be  destructive,  but  there  is  no  reason  to 
suppose  that  this  series  of  accidents  occurs  at  all  frequently,  and  it  is 
impossible  to  diagnose  inefficiency  of  the  pancreatic  secretion. 

PREPARATIONS. 

Pancreatinum  (U.  S.  P.),  a  mixture  of  the  enzymes  naturally  existing  in 
the  pancreas  of  warm-blooded  animals,  usually  obtained  from  the  fresh  pan- 
creas of  the  pig.  It  forms  a  yellowish,  yellowish-white,  or  grayish,  amor- 
phous powder,  having  a  faint,  not  disagreeable  odor  and  a  meat-like  taste, 
and  is  slowly  soluble  in  water.  0.1-0.3  G.  (2-5  grs.),  in  powder  or  in  cap- 
gules.  Keratin  capsules  have  been  proposed  in  order  to  protect  the  pancre- 
atin from  the  gastric  juice. 

Liquor   Pancreatis   (B.   P.),    a   liquid   preparation   containing   the   digestive 


DIASTASE.  707 

principles  of  the  fresh  pancreas  of  the  pig.  The  preparation  is  most  active 
when  the  animal  from  which  it  has  been  obtained  has  been  fed  shortly  be- 
fore being  killed.  Two  cubic  centimetres  of  the  solution  ought  to  digest 
80  c.c.  of  milk. 

Benger's  Liquor  Pancreaticus  is  a  solution  of  the  pancreatic  ferments 
made  up  with  some  alcohol. 

In  connection  with  the  digestive  ferments  may  be  mentioned  ingluvin,  an 
extract  of  the  fowl's  gizzard,  which  was  a  few  years  ago  highly  recom- 
mended as  a  remedy  in  the  sickness  of  pregnancy,  but  has  proved  entirely 
valueless. 

Vegetable  Ferments. 

Besides  these  animal  digestive  ferments,  a  number  of  vegetable  proteolytic 
enzymes  are  known,  and  have  enjoyed  a  more  or  less  shortlived  popularity. 
Probably  many  more  plant  juices  are  able  to  digest  proteids  than  are  at 
present  generally  recognized  ;  thus  many  of  the  bacteria  liquefy  gelatin  and 
albumin,  and  the  insectivorous  plants  such  as  Drosera  (sundew)  and  Dionea 
secrete  a  digestive  fluid.  Figs,  pine-apples  (bromeliri),  the  scarlet  pimpernal 
(Anagallis  arvensis),  and  many  others  of  the  higher  plants  have  been  shown 
to  possess  these  ferments,  but  the  best  known  of  these  is  the  Carica  papaya, 
or  pawpaw,  which  contains  a  digestive  ferment  known  as  papain,  papayotin 
or  papoid.  This  ferment  acts  in  neutral,  moderately  acid,  or  alkaline  solu- 
tion at  the  temperature  of  the  body  and  in  the  cold.  When  swallowed  it 
has  no  effect  except  its  digestive  action,  but  injected  into  the  blood,  it  is 
said  to  paralyze  the  heart  and  central  nervous  system,  and  to  cause  haemor- 
rhages into  the  intestine  ;  it  is  very  irritant  in  the  subcutaneous  tissues, 
causing  pain  and  high  fever.  It  has  been  used  instead  of  pancreatin  and 
pepsin  in  disorders  of  the  digestion,  and  also  as  an  anthelmintic.  Diphthe- 
ritic membranes  have  been  treated  by  the  frequent  application  of  papain 
solution  (once  an  hour  by  some  of  its  advocates,  more  frequently  by  others), 
and  apparently  with  success  as  far  as  the  removal  of  the  membrane  was 
concerned ;  the  underlying  disease  was  not  favorably  influenced,  however, 
and  the  treatment  has  been  abandoned.  Papain  solution  has  also  been  in- 
jected by  the  hypodermic  needle  into  tumors  and  abscesses,  with  the  intention 
of  digesting  the  new  growth,  or  accelerating  the  progress  of  the  abscess 
towards  the  surface,  but  the  results  obtained  do  not  encourage  the  further 
use  of  the  remedy  in  this  way.  Peptones  are  unquestionably  formed  in  the 
tumors  when  papain  is  injected. 

Several  milk-curdling  ferments  have  been  found  in  plants,  but  none  of 
them  have  been  used  in  therapeutics. 

Diastase. 

Several  amylolytic  or  sugar- forming  ferments  have  been  used  more 
or  less  in  therapeutics,  the  first  of  these  being  the  diastase  or  enzyme  of 
malty  which  is  known  under  the  names  of  malt  extract,  maltzyme, 
maltine,  etc.  When  grain  is  allowed  to  germinate,  its  starch  is  formed 
into  a  soluble  form  (sugar)  by  means  of  a  ferment  known  as  diastase, 
and  it  was  supposed  that  this  diastase  might  aid  the  digestion  of  starchy 
foods  in  the  body.  When  malt  extract  is  formed  at  a  low  temperature, 
it  unquestionably  contains  diastase  and  is  capable  of  digesting  starch, 
but  many  of  the  extracts  on  the  market  are  quite  inert,  the  ferment 
having  been  destroyed  by  heat.  Those  extracts  are  therefore  devoid 
of  digestive  power,  but  form  a  pleasant,  easily  digested  food.  They 
often  contain  alcohol,  and  are  then  indistinguishable  from  beer  or  stout. 


708  FERMENTS,  SECRETIONS  AND  TOXALBUMINS. 

More  recently,  some  other  sugar-forming  ferments  have  been  brought 
forward,  notably  that  obtained  from  Eurotium  oryzse,  a  mould  of  the 
aspergillus  family.  This  enzyme  is  known  as  taka-diastase  from  the 
name  of  its  discoverer,  Takamine,  and  is  very  much  more  powerful 
than  any  of  the  malt  extracts,  as  it  digests  over  one  hundred  times  its 
weight  of  starch.  Taka-diastase  has  been  recommended  in  cases  in 
which  there  is  supposed  to  be  a  deficient  digestion  of  starch.  It  ceases 
to  act  in  the  gastric  juice  as  soon  as  the  acidity  exceeds  0.1  per  cent., 
but  may  be  able  to  digest  a  certain  amount  of  starch  in  the  mouth  and 
stomach  before  it  is  destroyed.  The  question  at  once  arises,  however, 
whether  the  ordinary  digestive  juices  are  ever  unable  to  digest  the 
starch  of  the  food.  And  although  a  new  term,  "  amylaceous  dyspep- 
sia," has  been  introduced  to  indicate  this  class  of  cases,  if  they  should 
be  found  to  exist,  it  must  be  admitted  that  no  satisfactory  evidence  of 
their  existence  has  been  brought  forward  as  yet.  It  is  stated  that 
more  starch  is  found  to  be  digested  in  the  stomach  after  the  administra- 
tion of  diastase,  but  this  seems  to  be  beside  the  point,  for  it  merely 
indicates  that  less  starch  reaches  the  intestine  for  the  pancreatic  juice 
to  act  upon.  Until  it  is  shown  that  in  some  cases  the  digestion  of 
starch  by  the  intestinal  ferments  is  insufficiently  performed,  the  diastase 
preparations  would  seem  to  be  superfluous.  According  to  Friedenwald, 
diastase  increases  the  digestion  of  starch  in  the  stomach  chiefly  in  cases 
of  hyperacidity,  but  doubt  is  thrown  on  this  statement  by  other  in- 
vestigators. 

BIBLIOGRAPHY. 
Papain. 

Hirsch.     Therap.  Mon.,  1894,  p.  609. 

Oswald.     Munch,  med.  Woch.,  1894,  p.  665. 

Rossbach.     Ztschr.  f.  klin.  Med.,  vi.,  p.  527. 

Martin.     Jour,  of  Phys.,  y.,  p.  213  ;  vi.,  p.  336. 

Younger.     Lancet,  1895,  i.,  p.  1050. 

Chittenden,  Mendel  and  McDermott.     Amer.  Journ.  of  Phys.,  i.,  p.  255. 

Pineapple. 

Chittenden.     Jour,  of  Phys.,  xv.,  p.  249. 

Taka-Diastase. 

Friedenwald.     New  York  Med.  Journ.,  1897,  May  29. 
Leo.     Therapeut.  Monatsh.,  1896,  p.  635. 
Strauss  u.  Stargardt.     Ibid.,  1898,  p.  65. 

II.     BILE. 

The  bile  is  very  seldom  used  in  therapeutics  at  the  present  day,  al- 
though it  was  formerly  credited  with  great  healing  virtues.  It  has 
a  bitter  taste,  and  may  have  some  effect  like  the  vegetable  bitters,  but 
has  no  advantage  over  these,  and  is  not  likely  to  be  used  to  promote 
the  appetite  now,  although  it  was  formerly  used  as  a  stomachic.  The 
bile  is  found  to  precipitate  the  peptones  in  test-tube  experiments,  but 
does  not  appear  to  retard  digestion  in  the  stomach  materially,  judging 
from  experiments  carried  out  in  a  case  of  gastric  figtula.  In  the  intes- 
tine it  is  generally  believed  to  act  as  an  antiseptic,  chiefly  because  the 


BILE.  709 

stools  have  a  strong  putrefactive  odor  in  cases  of  retention  of  bile. 
Limbourg  has  also  shown  that  the  addition  of  bile  to  proteid  solutions 
delays  their  decomposition,  while  there  is  some  evidence  that  it  promotes 
pancreatic  digestion.  It  has  some  purgative  action,  as  is  shown  by  the 
obstinate  constipation  which  often  occurs  when  it  is  prevented  from 
reaching  the  intestine ;  according  to  Stadelmann,  the  bile  acids  irritate 
the  mucous  membrane  of  the  large  bowel  and  thus  induce  purgation. 
An  obscure  relation  exists  between  the  drastic  purgatives  and  the  bile 
in  the  intestine,  several  of  them  failing  to  act  in  its  absence.  (See 
page  96.)  Bile  increases  the  activity  of  the  fat-splitting  ferment  of  the 
pancreas  and  thus  augments  the  absorption  of  fats.  Most  of  the  bile 
given  by  the  mouth  is  absorbed  in  the  stomach  and  small  intestine  and 
carried  to  the  liver,  which  excretes  it  again,  while  a  small  quantity  of  the 
bile  acids  escapes  in  the  urine.  In  the  liver  it  increases  the  secretion 
of  both  the  fluid  and  the  solids  of  the  bile ;  in  fact,  the  bile  is  the  only 
reliable  cholagogue  known.  The  constituent  which  acts  on  the  secre- 
tory liver  cells  seems  to  be  the  bile  acids,  and  their  increase  is  greater 
than  can  be  accounted  for  merely  by  the  excretion  of  that  administered, 
so  that  it  would  seem  that  they  exercise  some  specific  stimulant  action  on 
the  secretory  cells.  The  bile  pigment  is  also  augmented  when  bile 
acids  are  absorbed,  owing  to  the  destruction  of  the  red  cells  of  the 
blood,  as  the  liberated  haemoglobin  is  carried  to  the  liver  and  there 
formed  into  bile  pigment. 

Bile  given  by  the  mouth  does  not  cause  any  symptoms  except  those 
from  the  intestine  and  liver.  When  it  is  injected  into  the  blood,  how- 
ever, it  depresses  the  central  nervous  system  and  the  heart  muscle  from 
its  direct  action  on  these  organs,  and  decomposes  the  red  cells  of  the 
blood.  Muscles  and  nerves  suspended  in  a  solution  of  bile  salts  rapidly 
lose  their  irritability,  and  some  unicellular  organisms  are  killed  and 
dissolved  by  them.  The  poisonous  constituent  of  the  bile  seems  to  be 
the  salts  of  the  bile  acids,  but  several  authors  have  stated  that  the 
pigment  is  also  active. 

Fraser  has  recently  discovered  that  the  bile  has  considerable  virtue 
as  an  antitoxin.  Thus  the  bile  of  the  venomous  snake  acts  as  an 
antidote  to  their  poison,  and  the  bile  of  other  animals  has  also  some 
effect  in  this  direction.  This  antitoxic  action  is  apparently  due  to  the 
presence  in  the  bile  of  cholesterin,  which  forms  a  loose  combination  or 
solution  with  the  toxins  and  retards  their  absorption  into  the  cells. 
It  is  much  more  efficient  when  it  is  mixed  with  the  poison  before  its 
application,  than  when  it  is  injected  after  the  bite.  Frazer  adds  that 
the  bile  is  also  an  antitoxin  to  other  poisons,  including  those  produced 
by  the  pathogenic  microbes.  Others  have  found  that  the  bile  of  ani- 
mals dying  of  an  infectious  disease  (rinderpest)  possesses  some  curative 
properties  in  other  animals  suffering  from  the  same  malady,  this  being 
explained  by  the  excretion  of  the  antitoxin  in  the  bile. 

Bile  has  been  used  as  a  purgative,  and  it  has  been  particularly 
recommended  in  the  form  of  an  enema.  It  does  not  seem  to  be  reli- 
able, however,  and  presents  no  advantages  over  soaps  and  similar  sub- 
stances. 


710  FERMENTS,   SECRETIONS  AND   TOXALBUMINS. 

As  a  cholagogue  it  is  without  rival,  but  no  condition  is  known  in 
which  an  increase  of  the  bile  secretion  is  indicated,  for  though  it  has  been 
proposed  to  expel  gall-stones  by  raising  the  pressure  in  the  gall-ducts  by 
cholagogues,  it  is  found  that  when  the  pressure  is  only  slightly  in- 
creased, the  secretion  is  arrested.  It  is  inconceivable  that  the  small 
rise  in  pressure  could  force  out  an  impacted  gall-stone. 

Bile  might  be  used  to  aid  the  absorption  of  fats,  particularly  when 
it  is  deficient  in  the  bowel ;  in  a  case  of  biliary  fistula  Joslin  found  that 
much  less  fat  and  nitrogenous  food  escaped  in  the  stools  when  the 
patient  was  treated  with  bile  pills,  than  when  no  treatment  was  adopted. 

PREPARATIONS. 

Pel  Sovis  (U.  S.  P.),  ox  gall,  the  fresh  bile  of  the  ox. 

Fel  Sovis  Purificatum  (U.  S.  P.),  Fel  Bovinum  Purificatum  (B.  P.),  is  formed 
from  the  fresh  bile  by  the  addition  of  alcohol,  filtration  and  evaporation  to 
pillular  consistency.  The  alcohol  is  added  to  remove  the  mucus  of  the  bile. 
The  pigments  may  be  removed  by  filtering  the  watery  solution  through  ani- 
mal charcoal. 

Bile  is  always  prescribed  in  the  form  of  pills  made  from  the  purified  prep- 
aration. 0.3-1  G.  (5-15  grs.). 

BIBLIOGRAPHY. 

Stadelmann.  Arch.  f.  exp.  Path.  u.  Pharm.,  xxxvii.,  p.  352.  Ztschr.  f.  Biolog., 
xxxiv.,  p.  1. 

Rywosch.     Arb.  a.  d.  pharm.  Instit.  zu  Dorpat,  ii.,  p.  102  ;  vii.,  p.  157. 

Limbourg.     Ztschr.  f.  phys.  Chem.,  xiii.,  p.  196. 

Pfaffand  Balch.     Journ.  of  Exp.  Med.,  ii.,  p.  49. 

Fraser.     Brit.  Med.  Journ.,  1897,  ii.,  pp.  125  and  595  ;  1898,  ii.,  p.  627. 

Joslin.     Journ.  of  Exp.  Med.,  v.,  p.  513. 

Cohnheim.     Biochem.  Centralbl.,  i.,  p.  171. 

III.     INTERNAL   SECRETIONS. 

Until  very  recently  the  only  animal  secretions  recognized  in  thera- 
peutics were  the  digestive  ferments,  the  bile,  and  a  few  rarely  used  sub- 
stances, such  as  musk.  But  within  the  last  few  years  it  has  been 
shown  that  certain  glands  supply  the  blood  constantly  with  substances 
which  are  necessary  to  the  economy,  and  a  deficiency  in  which  leads  to 
the  gravest  symptoms.  The  subject  of  internal  secretion  is  still  in  its 
infancy,  but  therapeutics  has  already  been  enriched  with  at  least  two 
additions  of  unquestioned  value,  and  may  profit  still  more  by  the  fur- 
ther exploration  of  this  field.  The  chief  object  of  "  organotherapeu- 
tics,"  or  the  treatment  of  disease  with  extracts  of  the  glands  of  the 
body  (animal  extracts),  has  been  to  supply  a  deficiency  of  the  normal 
secretion.  At  the  same  time,  it  is  possible  that  a  wider  field  of  useful- 
ness may  be  developed,  for  there  is  no  reason  why  these  animal  extracts 
should  not  have  a  true  pharmacological  action,  as  well  as  the  vegetable 
extracts.  Advance  in  organotherapeutics  is  not,  however,  to  be  ex- 
pected from  the  indiscriminate  use  of  the  gland  extracts  in  every,  sort 
of  disease,  such  as  is  too  popular  at  present.  Such  progress  as  has 
been  made  hitherto  in  this  field  has  been  due  to  careful  observation 
and  experiment,  and  not  to  haphazard  use  of  the  hypodermic  syringe. 


THYROID  EXTRACT.  711 

Thyroid  Gland. 

The  treatment  of  certain  diseases  by  the  administration  of  thyroid 
gland  and  its  extracts  is  one  of  the  most  satisfactory  examples  of  ra- 
tional therapeutic  progress,  and  the  steps  which  led  to  its  adoption  may 
therefore  be  briefly  mentioned.  In  1882-3,  Kocher  and  Reverdin 
published  observations  made  on  patients  whose  thyroids  had  been  totally 
extirpated,  and  who  had  subsequently  presented  a  series  of  symptoms 
to  which  these  observers  gave  the  name  of  cachexia  thyreopriva.  They 
pointed  out  that  this  condition  resembled  in  many  of  its  features 
myxoedema,  a  disease  discovered  by  Gull  some  years  before  and  asso- 
ciated with  atrophy  of  the  thyroid  gland.  These  observations  were 
confirmed  by  a  number  of  authors,  who  removed  the  thyroids  from 
animals,  and  found  a  cachexia  appear  in  them.  The  next  advance 
was  the  discovery  that  these  symptoms  in  animals  could  be  removed, 
or  at  any  rate  ameliorated,  by  grafting  pieces  of  thyroid  in  the  peritoneal 
cavity  or  subcutaneous  tissue.  Horsley  suggested  that  myxoedema 
should  be  treated  in  the  same  way,  and  Murray  soon  afterwards  intro- 
duced the  treatment  of  this  disease  by  the  subcutaneous  injection  of 
thyroid  juice.  Even  in  his  first  case,  the  results  were  eminently  satis- 
factory, but  it  was  soon  found  that  the  same  results  could  be  obtained 
by  administration  by  the  stomach,  and  a  large  number  of  cases  have 
now  been  recorded  in  which  very  favorable  results,  or  even  the  complete 
disappearance  of  the  symptoms  has  followed  this  medication.  These 
include  not  only  myxoedematous  patients,  but  also  cases  in  which  the 
thyroid  was  removed  by  surgical  operation,  or  where  its  disease  gave 
rise  to  symptoms.  That  the  favorable  results  are  due  to  the  treat- 
ment is  proved  conclusively  by  the  return  of  the  symptoms  when  it  is 
abandoned. 

The  effect  of  the  thyroid  extract  could  be  explained  only  by  the 
presence  of  some  unknown  principle,  for  the  preparation  of  course  con- 
tained no  living  cells.  In  the  last  few  years,  numerous  researches 
have  been  carried  out  with  the  object  of  isolating  this  principle.1  It 
is  found  in  the  colloid  contents  of  the  gland  follicles  in  the  form  of 
a  globulin,  thyreoglobulin,  which  may  be  extracted  from  the  colloid 
and  gives  the  ordinary  proteid  reactions,  but  is  characterized  by  con- 
taining a  small  percentage  of  iodine ; 2  Baumann's  detection  of  this  ele- 
ment in  the  thyroid  gland  was  the  first  intimation  that  it  existed  in  the 
tissues  of  the  higher  animals  and  man.  Thyreoglobulin  is  not  com- 
pletely saturated  with  iodine,  for  it  forms  a  higher  combination  with  it 
in  the  test-tube,  but  then  loses  its  specific  action  on  the  animal  organ- 
ism. When  it  is  subjected  to  artificial  digestion  it  forms  albumoscs 
and  an  insoluble  non-proteid  substance  known  as  lodothyrinf  which 

*No  attempt  is  made  to  follow  the  chronological  order  of  these  researches. 

2  Sometimes  a  thyreoglobulin  is  found  in  the  gland,  which  resembles  the  normal  in  its 
reactions,  but  contains  no  iodine  (Oswald). 

3  lodothyrin  was  at  first  named  Thyroiodin,  but  this  was  liable  to  be  confused  with 
thyreoidin,  a  term  used  to  indicate  the  simple  extract  of  the  gland. 


712  FERMENTS,   SECRETIONS  AND   TOXALBUMINS. 

contains  practically  all  the  iodine  of  the  gland.  A  similar  result  is 
obtained  by  acting  on  thyroid  gland,  colloid,  or  thyreoglobulin  with 
acids.  lodothyrin  is  readily  dissolved  in  dilute  alkaline  solutions  and 
may  be  reprecipitated  by  acids.  It  contains  more  iodine  than  thyreo- 
globulin of  course,  but  the  exact  percentage  is  still  a  disputed  point, 
for  while  Baumann  originally  stated  that  it  contained  about  ten  per 
cent.,  others  have  found  it  as  low  as  four  per  cent.,  and  Oswald's  analy- 
sis gives  no  less  than  fourteen  per  cent,  for  iodothyrin  obtained  by  the 
action  of  acids,  and  about  five  per  cent,  for  that  formed  by  digestion. 
Much  remains  to  be  done,  therefore,  before  the  composition  of  iodo- 
thyrin can  be  definitely  settled,  but  it  is  certain  that  it  is  not  a  proteid 
and  that  it  is  rich  in  iodine  and  nitrogen,  while  sulphur  is  present  in 
smaller  amount,  and  phosphorus  is  not  contained  in  the  molecule. 

The  amount  of  iodothyrin  in  the  gland  varies  a  good  deal  in  differ- 
ent animals,  and  in  different  individuals  of  the  same  species.  It  was  at 
first  supposed  that  in  the  goitre  districts  the  percentage  of  iodothyrin 
in  the  gland  was  lower  than  in  healthy  areas,  and  that  in  cases  of 
goitre  the  percentage  was  smaller  than  in  normal  individuals,  but  this 
seems  to  be  incorrect,  no  relation  existing  apparently  between  the  amount 
of  iodine  in  the  thyroid  and  the  presence  of  endemic  goitre.  In  children 
less  iodine  is  found*  in  the  gland  than  in  adults,  and  after  middle  age 
it  lessens  again.  Meat  diet  diminishes  the  amount  of  iodine,  either 
because  it  makes  greater  demands  on  the  supply,  or  because  too  little 
iodine  is  ingested  in  the  food.  Vegetable  foods,  especially  those  con- 
taining much  iodine,  such  as  beetroot  and  probably  the  marine  algse, 
increase  the  iodine  of  the  thyroid  gland.  Iodine  given  medicinally 
also  augments  it,  and  not  only  iodine  itself,  but  various  combinations, 
such  as  iodoform  and  iodides.  It  is  not  yet  determined  whether 
actually  more  iodothyrin  is  formed  under  these  conditions,  or  whether 
that  already  present  contains  more  iodine. 

A  number  of  other  constituents  have  been  isolated  from  the  thyroid 
gland  in  a  condition  of  greater  or  less  purity,  some  of  them  proteids 
and  others  crystalline  non-pro teid  bodies ;  but  none  of  them  possess 
the  specific  action  of  the  gland  extract  and  in  fact  none  of  them  have 
been  shown  to  induce  any  effect  at  all  except  those  which  it  may  be 
supposed  contained  iodothyrin.  On  the  other  hand,  thyreoglobulin 
and  iodothyrin  induce  the  same  effects  as  the  extract  both  in  myxce- 
dema  and  goitre  in  man  and  in  excision  of  the  thyroid  in  animals.  This 
has  been  disputed  until  recently,  owing  to  the  fact  that  in  many  cases 
the  parathyroid  glands  have  been  removed  along  with  the  thyroid  in 
animal  experiments.  Now  the  removal  of  the  parathyroids  in  dogs 
(on  which  the  experiments  have  generally  been  performed)  leads  to  a 
series  of  symptoms  arising  from  the  central  nervous  system,  and  these 
are  not  affected  by  thyroid  medication.  When  the  thyroid  alone  is 
removed,  the  symptoms  are  relieved  by  iodothyrin,  thyreoglobu- 
lin, or  thyroid  extract.  lodothyrin,  therefore,  represents  the  whole 
therapeutic  virtues  of  thyroid  extract,  although  it  is  possible  that  the 
gland  may  have  other  functions  than  its  secretion.  lodothyriii  and 


THYROID  EXTRACT.  713 

thyroid  extracts  are  thus  used  to  replace  the  secretion  of  the  thyroid 
gland,  when  it  is  deficient  from  any  cause.  The  function  of  the  thy- 
roid gland  is  still  very  obscure,  however,  although  it  is  now  certain 
that  it  is  of  great  importance  in  the  metabolism,  as  is  clearly  shown  by 
the  disastrous  results  of  its  removal  or  atrophy.  The  results  of  the 
injection  of  the  thyroid  extract  have  also  thrown  much  light  on  the 
working  of  this  mysterious  organ. 

Action. — The  thyroid  extracts  and  iodothyrin  seem  to  be  devoid  of 
effect  in  many  normal  animals  and  patients,  unless  when  given  in  enor- 
mous quantities.  In  others  they  cause  some  unpleasant  symptoms, 
Vvhich  occur  more  especially  in  myxoedema  and  goitre.  These  symp- 
toms are  partly  subjective  and  indefinite,  such  as  headache,  wandering 
pains,  or  general  weakness,  while  others  are  evidently  due  to  circula- 
tory changes,  and  consist  of  a  feeling  of  fullness  and  congestion  of  the 
head,  palpitation  of  the  heart,  and  acceleration,  sometimes  weakness, 
of  the  pulse.  Tremors  in  the  arms  and  legs  point  to  changes  in  the 
central  nervous  system,  while  loss  of  appetite  and  diarrhoea  indicate 
that  the  alimentary  canal  is  not  exempt  from  its  influence.  Perspira- 
tion is  often  complained  of,  especially  in  myxoedema,  and  a  rise  of 
temperature  also  occurs  not  infrequently. 

In  normal  animals  iodothyrin  injected  intravenously  in  large  quan- 
tities generally  accelerates  the  heart  and  lowers  the  blood-pressure 
somewhat,  and  even  when  given  by  the  mouth  repeatedly  for  several 
days,  it  causes  some  acceleration.  This  acceleration  of  the  heart  has 
been  attributed  by  some  investigators  to  stimulation  of  the  accelerator 
centre,  by  others  to  direct  action  on  the  heart ;  it  does  not  seem  to  be 
due  to  any  changes  in  the  inhibitory  apparatus. 

Loss  of  flesh  and  thirst  have  been  observed,  even  when  the  appetite 
is  good  and  sufficient  food  and  water  are  supplied.  The  urine  is  uni- 
formly increased  in  amount.  A  number  of  observers  have  found 
that  the  continued  administration  to  animals  of  thyroid  preparations  in 
large  amounts  leads  to  diarrhoea,  muscular  weakness,  especially  in  the 
hind  extremities,  emaciation,  gastro-enteritis,  nephritis,  and  fatty  degen- 
eration of  various  organs.  In  other  instances  no  such  symptoms  have 
been  elicited,  the  animals  remaining  perfectly  normal  after  prolonged 
treatment. 

Some  of  the  symptoms  induced  in  man  by  an  overdose  of  thyroid 
resemble  those  seen  in  exophthalmic  goitre  or  Graves'  (Basedow's) 
disease,  and  exophthalmos  has  been  observed  in  monkeys  to  which 
large  amounts  of  thyroid  were  given. 

As  may  be  gathered  from  the  above,  great  discrepancies  occur  in  the 
accounts  of  the  effects  of  thyroid  on  normal  animals.  The  accelera- 
tion of  the  heart  and  jthe  .fall  in  weight  seem  to  be  the  most  common 
results. 

The  effects  of  thyroid  extract  on  the  Metabolism  have  been  repeat- 
edly examined,  with  very  uniform  results.  One  of  the  most  striking 
features  in  many  individuals  is  the  rapid  loss  of  weight,  which  often 
amounts  to  several  pounds  per  week.  Another  is  the  increase  in  the 


714  FERMENTS,   SECRETIONS  AND   TOX ALBUMINS. 

amount  of  nitrogen  in  the  urine,  which  occurs  both  in  goitre  and 
myxoedema,  and  very  often  in  apparently  normal  persons.  More  ni- 
trogen is  excreted  in  the  urine  frequently  than  is  taken  in  the  food, 
that  is  to  say,  the  iodothyrin  leads  to  the  destruction  of  the  proteids  of 
the  tissues.  If  more  nitrogenous  food  be  given,  however,  this  may  be 
arrested,  and  in  fact  if  large  quantities  of  meat  be  taken,  less  nitrogen 
may  be  excreted  than  is  taken  in  the  food,  so  that  although  the  patient 
is  losing  in  weight,  he  may  be  actually  increasing  in  nitrogenous  tis- 
sue. If,  on  the  other  hand,  a  patient  has  been  put  in  nitrogenous 
equilibrium,  and  then  under  iodothyrin  begins  to  excrete  more  nitro- 
gen than  he  ingests,  this  excessive  tissue  waste  is  not  stayed  by  in- 
creased carbohydrates  and  fats ;  that  is,  the  carbohydrates  and  fats 
cannot  replace  nitrogenous  food  to  the  same  extent  as  in  normal  individ- 
uals. Iodothyrin  has  thus  a  specific  effect  in  increasing  the  waste  of 
the  proteids  of  the  body.  But  this  increased  waste  of  the  proteids 
only  accounts  for  about  one-sixth  of  the  loss  of  weight,  the  other  five- 
sixths  being  evidently  due  to  the  more  rapid  oxidation  of  fats  and  the 
removal  of  fluid  from  the  body.1  The  more  rapid  oxidation  is  further 
evidenced  by  the  increased  amount  of  oxygen  absorbed  and  of  carbonic 
acid  exhaled  by  the  lungs  in  cases  of  myxoedema  and  sometimes  in 
obesity  and  goitre  treated  with  the  extract.  The  removal  of  fluid  from 
the  body,  perhaps  the  most  potent  factor  in  reducing  the  weight  in 
these  cases,  is  shown  by  diuresis,  which  occurs  in  myxredema  especially, 
but  also  in  obesity.  This  diuresis  has  been  ascribed  to  some  specific 
action  on  the  kidney,  or  to  the  changes  in  the  circulation,  but  may  per- 
haps be  due  to  the  increased  excretion  of  urea  and  other  urinary  sub- 
stances. That  the  kidney  is  acted  on  in  some  cases  is  shown  by  the 
occasional  appearance  of  albumin  in  the  urine  of  patients  treated  with 
thyroid  preparations. 

The  phosphates  excreted  are  increased  in  the  same  ratio  as  the  nitro- 
gen, and  the  increase  is  obviously  due  to  the  same  cause,  augmented 
proteid  waste. 

In  some  cases  sugar  has  been  found  in  the  urine  after  thyroid  treat- 
ment, and  in  a  considerable  percentage  of  persons  it  seems  to  cause  a 
tendency  to  glycosuria,  as  is  shown  by  the  appearance  of  sugar  in  the 
urine  after  the  ingestion  of  large  quantities  of  sugar,  which  would 
normally  be  oxidized  in  the  tissues.  The  uric  acid  excretion  does  not 
seem  to  be  materially  affected  by  thyroid  treatment. 

After  iodothyrin  has  been  administered,  iodine  is  found  in  the  urine 
in  the  form  of  iodides,  so  that  the  iodothyrin  is  evidently  decomposed, 
at  any  rate  in  part,  in  the  body.  The  rest  of  the  iodine  is  taken  up 
by  the  thyroid  gland,  and  it  would  appear  probable  that  it  enters  into 

1  Schondorff  states  that  in  nitrogenous  equilibrium  the  oxidation  of  the  fats  is  in- 
creased before  the  proteids  of  the  body  are  attacked,  but  when  the  fat  destruction  has 
reached  a  certain  point,  the  proteid  waste  is  also  increased.  The  early  augmentation  of 
the  nitrogen  of  the  urine  does  not  indicate  an  acceleration  of  the  proteid  metabolism, 
but  is  due  to  the  removal  of  urea  and  other  products,  which  have  been  formed  in  the 
tissues  before  the  administration  of  the  remedy,  but  which  are  now  excreted  through 
the  increased  activity  of  the  kidneys. 


THYROID  EXTRACT. 


715 


it  in  the  form  of  iodothyrin,  and  that  no  preliminary  decomposition 
occurs  here. 


In  regard  to  their  reaction  to  thyroid  medication,  individuals  vary  consid- 
erably, for  many  are  scarcely  affected  by  it  in  any  way,  and  this  is  particu- 
larly true  of  children,  while  others  lose  weight  rapidly,  and  under  larger 
doses  show  symptoms  of  poisoning  (thyroidism).  These  seem  to  be  more 
easily  elicited  in  goitre  and  myxoedema  than  in  ordinary  cases.  On  the 
other  hand,  in  Grave's  disease  the  symptoms  are  generally  aggravated  by 
thyroid  treatment,  although  a  few  cases  are  recorded  in  which  it  gave  relief. 
Many  authorities  therefore  believe  that  Grave's  disease  is  due  to  the  over- 
production of  iodothyrin,  but  this  has  not  yet  been  proved,  although  there 
is  considerable  support  for  the  theory. 


FIG.   51. 


FIG.   52. 


A  case  of  sporadic  cretinism.  Fig.  51,  before  treatment,  age  23  months,  height  28  inches,  cir- 
cumference of  the  abdomen  19  inches.  Fig.  52  after  treatment  with  thyroid  extract  for  5%  months, 
height  30  inches,  circumference  of  abdomen  15  inches.  (OSLER.  ) 

The  fact  that  ''thyroidism"  occurs  more  frequently  in  myxcedematous 
than  in  normal  persons  seems  difficult  of  explanation,  but  it  has  been  sug- 
gested that  the  symptoms  are  due  not  to  the  iodothyrin  itself,  but  to  the 
products  of  its  action.  It  may  be  supposed  that  in  myxoedema  a  large 
amount  of  some  substance  accumulates  in  the  tissues,  because  the  iodothyrin 
is  not  present  in  sufficient  quantity  to  decompose  it,  and  that  when  the  thy- 
roid treatment  is  commenced,  the  body  is  flooded  with  the  products  of  de- 
composition and  these  give  rise  to  symptoms.  In  normal  persons,  on  the 
other  hand,  there  is  no  such  accumulation,  and  iodothyrin  therefore  induces 
no  symptoms  until  it  is  given  in  such  quantity  as  to  induce  intoxication  it- 


716  FERMENTS,   SECRETIONS  AND   TOXALBUMINS. 

self.  In  Grave's  disease  the  iodothyrin  would,  of  course,  tend  to  aggravate 
the  symptoms,  if  these  are  due  to  its  excessive  production.  Until  more  is 
learned  of  the  action  of  iodothyrin  and  of  the  cause  of  Grave's  disease,  how- 
ever, these  explanations  are  mere  hypotheses,  and  they  need  not  be  entered 
upon  farther  here. 

Iodine,  as  has  been  stated,  increases  the  iodothyrin  of  the  gland,  and  this 
perhaps  explains  the  beneficial  effects  formerly  seen  in  goitre  from  the  applica- 
tion of  iodine  internally  and  locally.  When  iodine  was  efficient  in  those 
cases,  and  any  considerable  diminution  of  the  gland  occurred,  it  was  often 
accompanied  by  symptoms  exactly  resembling  those  produced  by  large  doses 
of  iodothyrin.  Those  symptoms  were  caused  by  small  quantities  in  some 
patients,  while  much  larger  doses  had  no  such  effects  in  others — a  fact  which 
gave  rise  to  some  discussion  and  several  erroneous  theories.  Sometimes  the 
acute  symptoms  passed  into  a  cachexia  of  very  long  standing.  The  quan- 
tity of  iodine  required  to  act  in  goitre  is  much  greater  than  the  iodine  of  the 
iodothyrin  necessary,  and  this  shows  that  the  latter  acts  not  merely  as  an 
iodine  compound,  but  as  the  specific  substance  of  the  gland.  Various  iodine 
compounds,  such  as  iodalbumin  and  iodospongin  (the  iodine  compound  of  the 
sponge)  have  been  shown  to  be  practically  inert  in  goitre.1 

PREPARATIONS. 

THYROIDEUM  SICCTTM  (B.  P.),  GLANDULE  THYROIDE^E  Sicc^:  (U.  S.  P.), 
a  powder  prepared  from  the  fresh  and  healthy  thyroid  gland  of  the  sheep.  It 
forms  a  light,  dull-brown  powder  with  a  faint,  meat-like  odor  and  taste,  free 
from  any  odor  of  putrescence.  About  16  grs.  represent  an  entire  gland.  Dose, 
0.2-0.6G.  (3-10  grs.). 

LIQUOR  THYROIDEI  (B.  P.),  a  liquid  prepared  from  the  fresh  and  healthy 
thyroid  gland  of  the  sheep,  and  containing  some  phenol.  A  pinkish,  turbid 
fluid,  entirely  free  from  any  odor  of  putrescence.  It  ought  to  be  freshly  pre- 
pared. 6  c.c.  (100  mins.)  represent  an  entire  thyroid  gland  (5-15  mins.). 

Thyroid  medication  may  be  carried  out  in  a  number  of  different  ways. 
The  old  method  of  ordering  the  raw  or  toasted  gland  to  be  taken  daily  may 
now  be  said  to  be  rendered  obsolete  by  more  elegant  preparations,  such  as 
dried  thyroid  or  thyroid  extract  in  powder  form  or  in  pills  or  tablets,  or  the 
liquor.  These  ought  not  to  be  prescribed  in  large  quantities  as  they  are 
liable  to  undergo  putrefaction  unless  when  carefully  kept ;  iodothyrin  tablets 
have  also  been  introduced,  each  containing  0.001  G.  (gV  gr.)  or  more  of  iodine. 
The  dose  should  be  small  at  first  (e.  </.,  J  gr.  of  the  dried  gland  or  2-3  mins. 
of  the  liquor  every  evening  for  the  first  week  of  treatment)  and  should  be 
gradually  increased,  until  improvement  sets  in  or  unpleasant  symptoms 
arise. 

Therapeutic  Uses.  —  Iodothyrin  is  not  a  dangerous  remedy,  unless  in 
certain  cases.  In  myxoedema,  however,  it  should  be  used  with  care, 
especially  if  the  heart  is  seriously  affected,  as  the  cardiac  muscle  may 
be  unable  to  meet  the  requirements  of  the  accelerated  rhythm  ;  several 
serious  cases  and  one  or  two  fatalities  have  already  been  recorded  in 
these  conditions. 

Iodothyrin  is  useful  as  a  substitute  for  the  normal  gland  secretion 

1  In  this  account  of  the  action  of  the  thyroid  extract  and  its  constituents,  the  gen- 
erally accepted  view  has  been  given,  namely,  that  the  thyroid  gland  secretes  a  substance 
into  the  blood  which  is  necessary  to  the  normal  life  of  the  organism.  It  must  be  added 
that  Blum  advocates  the  theory  that  the  thyroid  gland  retains  its  colloid  substance  in 
its  interior  and  employs  it  to  destroy  a  poisonous  proteid  formed  in  the  course  of  metab- 
olism. The  grounds  for  this  view  seem  quite  inadequate,  however,  and  the  reader  may 
be  referred  to  the  numerous  papers  of  Blum  on  the  subject. 


THYROID  EXTRACT.  717 

in  cases  where  the  latter  is  wanting  or  deficient,  as  in  myxoedema, 
cachexia  thyreopriva,  goitre  and  sporadic  cretinism.  In  all  of  these 
the  medication  has  to  be  continued  for  a  long  time,  perhaps  through- 
out life,  as  otherwise  the  patient  relapses  into  his  former  condition. 
The  decrease  in  weight  occurring  in  thyroid  medication  suggested  its 
use  in  obesity,  and  it  has  been  followed  by  some  loss  of  weight  in  a 
certain  number  of  cases,  especially  when  accompanied  by  proper  die- 
tetic treatment.  In  many  instances  it  has  had  little  or  no  eifect,  how- 
ever, and  the  initial  encouraging  action  is  seldom  maintained  when  the 
treatment  is  continued,  the  daily  loss  of  weight  gradually  becoming 
smaller  until  it  ceases  altogether.  The  amount  of  fat  actually  de- 
stroyed seems  to  be  trifling,  Magnus-Levy  estimating  that  about  one 
pound  disappears  in  ten  days,  which  is  much  less  than  can  be  got  rid 
of  by  judicious  exercise  and  an  appropriate  dietary.  Besides  the 
continued  use  of  thyroid  in  these  cases  is  not  altogether  devoid  of 
danger. 

In  some  skin  diseases,  especially  in  psoriasis,  it  has  been  of  benefit,  though 
not  by  any  means  invariably,  and  in  syphilis  of  old  standing  some  improve- 
ment has  been  seen.  This  is  probably  due  to  the  iodine  contained,  and  not 
to  the  specific  gland  secretion.  At  the  same  time  the  peculiar  combination 
in  which  the  iodine  is  present  may  perhaps  be  more  easily  made  use  of  by 
the  economy  than  the  ordinary  inorganic  preparations. 

The  improvement  seen  in  the  brain  symptoms  in  myxoadema  and  cretin- 
ism suggested  its  use  in  other  mental  diseases,  but  the  action  in  the  former 
is  due  to  its  substitution  for  the  normal  secretion,  and  little  or  no  effect  has 
followed  in  ordinary  cases  of  mental  disease. 

In  Graves'  disease  it  seems  generally  to  be  injurious.  A  curious  relation 
appears  to  exist  between  thyroid  and  the  thymus  gland,  for  the  administra- 
tion of  the  latter  is  often  attended  by  some  relief  in  this  disease. 

BIBLIOGRAPHY. 

Baumann  u.  Boos.     Ztschr.  f.  physiologische  Chemie,  xxi.,  xxii. 

Boos.     Ibid.,  xxi.,  xxii.,  xxv.,  pp.  1  and  242;  xxviii.,  p.  40. 

Baumann  u.  Goldmann.     Munch,  med.  Woch.,  1896,  p.  1153. 

Ewald.  Die  Erkrankungen  der  Schilddriise  —  Myxcedem  and  Cretinismus,  Wien, 
1896. 

Mbbius.  Die  Basedow' sche  Krankheit,  Wien,  1896.  These  two  are  contained  in 
Nothnagel's  Specielle  Pathologic  und  Therapie,  Bd.  xxii. 

Hutchison.  Brit  Med.  Journ.,  1896,  i.,  p.  722;  1897,  L,  p.  194.  Journ.  of  Phys., 
xx.,  p.  474;  xxiii.,  p.  178. 

Oswald.  Zts.  f.  phys.  Chem.,  xxiii.,  p.  265  }  xxvii.,  p.  14  ;  xxxii.,  p.  121 ;  Virchow's 
Arch.,  clxix.,  p.  444. 

Schondorff.     Pfliiger's  Arch.,  Ixiii.,  p.  423 ;  Ixvii.,  p.  395. 

Bensen.     Virchow's  Arch.,  clxx.,  p.  229. 

Maccallum.     Trans.  Assoc.  Amer.  Phys.,  xviii.,  p.  35. 

Treupel.     Munch,  med.  Woch.,  1896,  p.  117. 

Bleibtreu  u.   Wenddstadt.     Deutsch.  med.  Woch.    1895,  p«.  346. 

Zinn.     Berl.  klin.  Woch.,  1897,  p.  577. 

T>7  TY£1  "  1  A  1  1  "•  *r.Tk 


Blum.     Pfliiger's  Arch.,  Ixxvii.,  p.  70. 

Voit.     Ztschr.  f.  Biol.,  xxxv.,  p.  116. 

Cunningham.     Journ.  of  Exp.  Med.,  iii.,  p.  147. 

Magnus-Levy.     Ztschr.  f.  klin.  Med.,  xxxiii.,  p.  269. 

Donath.     Virchow's  Arch.,  cxliv.,  Supplem. ,  p.  253. 

Notkin.     Ibid.,  p.  224. 

Hellin.     Arch.  f.  exp.  Path.  u.  Pharm.,  xl.,  p.  121. 


718  FERMENTS,   SECRETIONS  AND  TOXALBUMINS. 

Howell,  Chiltenden,  Adami,  Putnam,   Kinnicutt  and  Osier.     Transactions  of  the  Con- 
gress of  American  Physicians  and  Surgeons,  iv.,  pp.  70-206. 
Berkeley.     Johns  Hopkins  Hospital  Bulletin,  1897,  p.  137. 
Cyon.     Pfluger's  Arch.,  Ixx.,  pp.  126,  511,  643. 
VerEecke.     Arch,  de  Pharmacodynam.,  iv.,  p.  81. 
Tambach.     Ztschr.  f.  Biol.,  xxxvi.,  p.  549. 

Anderson  u.  Bergmann.     Skand.  Arch.  f.  Physiol.,  viii.,  p.  326;  xiv.,  p.  224. 
Georgiewski.     Ztschr.  f.  klin.  Med.,  xxxiii.,  p.  153. 
Haskovec.     Arch,  internat.  de  Pharmacodyn. ,  viii.,  p.  167. 
Edmunds.     Proc.  Eoy.  Soc.,  Ixv.,  p.  368. 
Murray.     Practitioner,  1901,  April. 

Other  Internal  Secretions. 

Extract  of  the  Suprarenal  or  Adrenal  Glands.     See  p.  463. 

The  extracts  of  the  Pituitary  Body  or  rather  of  its  posterior  lobe  or  in- 
fundibular body,  cause  some  changes  in  the  circulation,  owing  to  their  con- 
taining two  substances  which  have  been  termed  the  pressor  and  depressor 
bodies.  The  arterial  tension  is  increased  by  the  extract  or  by  the  pressor 
body,  but  the  rise  is  smaller  than  that  induced  by  suprarenal  extract, 
although  it  is  maintained  longer.  The  renal  vessels  are  not  contracted  and 
some  diuresis  occurs.  The  heart  is  slowed,  partly  through  inhibitory 
action,  partly  from  direct  action  on  the  muscle.  The  depressor  body  causes 
a  transient  fall  in  the  blood-pressure.  The  hypodermic  injection  of  large 
quantities  of  the  extract  is  followed  by  paralysis  in  mammals.  Schiff 
found  that  extract  of  the  hypophysis  caused  a  marked  increase  in  the 
excretion  of  phosphates  in  a  case  of  acromegaly  and  in  a  healthy  old  man, 
while  it  had  no  effect  on  a  younger  individual ;  he  attributes  this  to  the  ex- 
tract tending  to  increase  the  destruction  of  the  bone  tissue.  Acromegaly  is 
generally  regarded  as  being  connected  in  some  way  with  disease  of  the  hy- 
pophysis, but  the  extract  does  not  seem  to  modify  the  disorder  in  most  cases, 
although  improvement  has  been  stated  to  occur  sometimes. 

The  Thymus  Gland  has  been  found  to  contain  minute  quantities  of  an 
iodine  compound,  which  may  be  identical  with  that  of  the  thyroid.  Svehla 
found  that  the  injection  of  an  extract  into  the  veins  caused  considerable  ac- 
celeration of  the  pulse  with  some  depression  of  the  blood-pressure.  The 
acceleration  was  found  to  be  due  to  direct  action  on  the  heart,  the  fall  of  the 
blood-pressure  to  paralysis  of  the  vaso-constrictors.  Very  large  quantities 
caused  restlessness,  collapse  and  death.  Thymus  extract  has  been  advised 
in  exophthalmic  goitre,  and  is  said  to  be  of  some  value  in  a  certain  number 
of  cases,  but  does  not  benefit  most  patients. 

The  excision  of  the  Pancreas  in  animals  is  followed  by  the  appearance  of 
sugar  in  large  quantity  in  the  urine,  and  in  many  cases  of  diabetes  in  the 
human  subject  the  pancreas  is  found  diseased,  so  that  this  gland  seems  to 
secrete  some  substance  which  is  required  by  the  tissues  to  enable  them  to 
maintain  the  normal  amount  of  sugar  in  the  blood.  Extract  of  pancreas  has 
therefore  been  administered  in  diabetes,  but  as  yet  without  satisfactory  re- 
sults in  the  ordinary  form  of  the  disease. 

Bone  Marrow  extract  and  Spleen  extract  have  been  given  in  pernicious 
anaemia  in  order  to  increase  the  number  of  the  red  cells,  and  many  other 
extracts  of  organs  have  been  proposed,  often  on  the  most  extraordinary 
grounds.  It  was  not  to  be  expected  that  these  extracts  of  brain,  heart,  liver, 
kidney,  prostate  and  lung  would  prove  of  benefit  in  the  diseases  of  these 
organs,  and  experience  has  shown  that  they  may  without  exception  be  rele- 
gated to  the  realms  of  quackery. 

One  extract  deserves  mention  on  account  of  the  attention  it  has  attracted, 
and  the  influence  it  has  had  on  the  theory  of  organotherapeutics — the  ex- 
tract of  the  Testicles.  The  use  of  testicular  extract  was  first  recommended 
by  Brown-Sequard  in  1889,  as  having  a  general  tonic  effect.  He  was  led  to 


OTHER  INTERNAL  SECRETIONS.  719 

this  conclusion  by  the  consideration  that  the  sexual  power  is  diminished  in 
advanced  life  and  made  the  bold  step  from  this,  that  one  of  the  causes  of  the 
woes  of  old  age  is  the  diminution  of  the  internal  secretion  of  the  testes ; 
this  elixir  of  youth  might,  however,  be  obtained  by  extracting  the  organs  in 
various  ways.  It  is  surprising  how  widely  this  theory  has  been  accepted, 
and  with  what  zeal  all  sorts  of  preparations  of  the  testicles  and  ovaries,  in- 
cluding the  unaltered  human  semen,  have  been  used,  in  therapeutics,  and,  it 
must  be  added  in  justice  to  the  observers,  in  experiments  upon  themselves. 
While  there  is  no  question  that  the  removal  of  these  organs  exercises  an  im- 
portant influence  on  a  number  of  organs  and  tissues,  there  are  no  sufficient 
grounds  for  believing  that  the  testicular  extract  has  any  effect  whatsoever 
except  through  hypnotic  suggestion.  Two  investigators  have  recently  at- 
tempted to  demonstrate  the  increase  in  the  muscular  strength  by  means  of 
the  ergograph,  but  the  results  obtained  by  means  of  this  instrument  in  other 
investigations  have  proved  so  deceptive,  that  little  weight  is  to  be  laid  on 
their  results.  Loewy  and  Richter  state  that  extract  of  testicle  increases  the 
oxidation  in  the  tissues  of  male  castrated  animals,  but  not  in  normal  male 
animals  or  in  castrated  females  ;  extract  of  ovary  (oophoriri)  has  a  similar 
effect  on  the  castrated  female. 

Instead  of  the  extract  of  testicle,  spermine,  an  alkaloid  found  in  the  testicle 
chiefly,  but  also  in  a  number  of  other  organs,  has  been  proposed  by  Poehl. 
According  to  this  author,  it  is  an  important  factor  in  the  oxidation  of  the 
tissues,  and  a  number  of  symptoms  of  disease  are  due  to  its  being  precipi- 
tated in  the  form  of  the  phosphate  and  thus  rendered  inactive,  this  being 
especially  liable  to  occur  whenever  the  alkalinity  of  the  blood  is  reduced  in 
any  way.  Poehl 's  spermine  has  therefore  been  advised  in  a  large  number 
of  diseases,  and  in  fact  is  considered  by  some  almost  a  panacea.  His  state- 
ments are  not  founded  on  any  satisfactory  experimental  or  clinical  observa- 
tions, and  have  met  with  little  credence  from  experienced  physicians.  Sper- 
mine was  at  one  time  supposed  to  be  identical  with  piperazine  but  this  has 
proved  to  be  erroneous. 

BIBLIOGRAPHY. 
On  Pituitary  Gland. 

Schafer  and  Oliver.     Journ.  of  Phys.,  xviii.,  p.  277. 
HowelL     Journ.  of  Exp.  Med.,  iii.,  p.  245. 
Schy.     Wien.  klin.  Woch.,  1897,  p.  277. 
Mairet  et  Bosc.     Arch,  de  Phys.  (5\  viii.,  p.  600. 
Cleghorn.     Amer.  Journ.  of  Phys.,  ii.,  p.  282. 
Schafer  and  Vincent.     Jour.  ofPhysiol.,  xxv.,  p.  87. 

On  Thymus  Gland. 

Svehla.     Arch.  f.  Exp.  Path.  u.  Pharm.,  xliii.,  p.  321. 
Kinnicutt.     Cong,  of  Amer.  Phys.  and  Surg.,  iv.,  p.  157. 

On  Testicular  Extract  (experimental). 

Zoth.     Pfl tiger's  Arch.,  Ixii.,  p.  335  ;  Ixix.,  p.  386. 

Pregl.     Ibid.,  Ixii.,  p.  379. 

Loewy  u.  Richter.     Arch.  f.  [Anat.  u.]  Phys.,  1899,  Suppl.,  p.  174. 

Dixon.     Journ.  of  Physiol.,  xxvi.,  p.  244. 

On  Spermine. 

Bubis.     Therap.  Monatsch.,  1896,  p.  22. 
Spitzer.     Berl.  klin.  Woch.,  1895,  p.  695. 
Poehl.     Ztschr.  f.  klin.  Med.,  xxvi.,  p.  135. 


720  FERMENTS,   SECRETIONS  AND   TOXALBUMINS. 

IV.     TOXALBUMINS. 

A  series  of  bodies,  whose  existence  has  only  been  recognized  in  the  last 
few  years,  but  whose  importance  in  medicine  is  ever  increasing,  is  that  of 
the  poisonous  proteids  or  toxalbumins.  The  idea  that  a  proteid  can  pro- 
duce dangerous  or  even  fatal  symptoms,  or  act  in  any  way  except  as  a  food, 
dates  only  from  1884,  but  many  of  the  animal  poisons  are  now  believed  to  be 
of  proteid  nature,  and  the  toxins  formed  by  the  micro-organisms  of  disease 
are  almost  certainly  of  the  same  general  class.  The  description  of  most 
of  these  must  be  relegated  to  the  text-books  on  bacteriology  and  pathology, 
but  some  toxalbumins  which  are  associated  with  drugs  in  daily  use  deserve 
short  mention. 

Ricin  is  an  intensely  poisonous  globulin  found  in  the  seeds  of  Ricinus 
communis  along  with  castor  oil,  which  does  not  itself  contain  this  principle, 
however.  Ricin  is  poisonous  in  doses  of  about  ^V  milligram  (T^V(7  gr-)  per 
kilogram  body  weight  when  it  is  injected  into  the  blood,  and  is  somewhat 
less  poisonous  when  applied  subcutaneously,  but  seldom  causes  any  symp- 
toms when  swallowed,  as  it  is  apparently  destroyed  for  the  most  part  by  the 
digestive  ferments.  It  is  thus  among  the  most  powerful  of  the  vegetable 
poisons  when  it  is  injected  directly  into  the  blood.  Death  often  occurs  only 
several  days  after  the  injection  in  animals,  and  in  the  interval  no  symptoms 
make  their  appearance  except  some  loss  of  appetite,  and  towards  the  end, 
diarrhoea  and  vomiting.  Post-mortem,  the  bowel  is  found  inflamed  and 
congested  and  contains  ecchymoses ;  blood  is  found  in  the  serous  cavities,  and 
extravasations  may  occur  in  various  other  organs,  although  not  so  uniformly 
as  in  the  bowel.  Among  the  most  obvious  lesions  are  the  innumerable 
ecchymoses  in  the  great  omentum  and  the  swelling  of  the  abdominal 
lymph-glands,  which  generally  contain  numerous  small  haemorrhages. 
Microscopical  examination  reveals  small  foci  of  necrosed  tissue  in  the 
liver,  spleen,  intestine,  stomach  and  other  organs.  Ricin  seems  to  be  ex- 
creted by  the  intestinal  epithelium,  which  may  explain  the  violence  of  its 
action  here,  although  it  acts  as  a  poison  in  many  other  tissues.  It  is  a 
powerful  irritant,  inducing  inflammation  and  suppuration  when  it  is  injected 
subcutaneously,  or  is  applied  to  the  conjunctiva.  On  the  other  hand  it  has 
little  or  no  irritant  action  on  the  mouth  and  throat,  and  is  digested  and 
rendered  harmless  in  the  stomach.  The  mucous  membrane  of  the  nose  is 
irritated  by  the  inhalation  of  the  powder  in  many  persons.  This  toxoglobu- 
lin  has  a  very  characteristic  action  on  the  blood.  When  a  drop  of  a  dilute 
solution  is  added  to  a  test-tube  of  defibrinated  blood,  the  corpuscles  soon 
fall  to  the  bottom,  leaving  the  clear  serum  above,  and  the  blood  does  not  filter 
through  paper  any  longer,  the  corpuscles  all  remaining  on  the  filter,  the  serum 
passing  through  colorless.  This  is  due  to  the  agglutination  of  the  red  cells, 
which  are  formed  into  masses  and  thus  fail  to  pass  through  the  pores  of  the 
filter.  Fibrin  does  not  seem  to  be  formed  in  the  process,  as  was  at  one  time 
supposed,  but  the  nature  of  the  cementing  substance  is  unknown.  Stillmark 
supposed  that  ricin  formed  these  masses  of  red  cells  in  the  blood  vessels,  and 
that  the  symptoms  were  due  to  the  emboli  resulting,  but  this  is  certainly  in- 
correct, for  the  blood  of  immune  animals  reacts  in  the  same  way,  yet  these 
are  not  poisoned  by  many  times  the  usual  fatal  dose  of  ricin. 

Ehrlich  found  that  animals  rapidly  acquired  immunity  to  the  action  of 
ricin,  if  they  received  for  some  time  small  non-toxic  doses.  From  this  dis- 
covery has  arisen  the  whole  of  serum-therapeutics,  which  plays  such  an  im- 
portant role  in  medicine  at  the  present  time.  By  gradually  increasing  the 
daily  amount  of  ricin,  rabbits  have  attained  an  immunity  of  5,000,  that  is, 
they  are  not  affected  by  5,000  times  as  much  ricin  as  would  have  killed 
them  had  no  preliminary  treatment  been  instituted.  This  immunity  is  en- 
tirely different  from  the  tolerance  acquired  for  morphine  and  other  drugs, 


TOXALBUMINS.  721 

for  the  latter  is  due  to  the  cells  of  the  body  becoming  accustomed  to  being 
constantly  bathed  in  a  fluid  containing  the  alkaloid.  The  same  tolerance 
is  acquired  by  various  marine  animals,  which  would  be  killed  if  suddenly 
changed  to  fresh  water,  but  which  are  gradually  acclimatized,  if  the  change  is 
made  more  gradually  by  adding  increasing  proportions  of  fresh  water  to 
the  sea  water  of  the  aquarium.  The  immunity  acquired  for  ricin  and  other 
toxalbumins  is,  on  the  contrary,  due  to  the  formation  in  the  body  of  a  sub- 
stance which  antagonizes  the  original  poison,  and  which  is  known  as  an 
antitoxin,  in  this  case  antiricin.  This  antagonistic  substance  circulates  in 
the  blood,  and  can  be  withdrawn  from  the  immune  animal  and  injected  into 
a  second,  which  then  acquires  a  certain  degree  of  immunity,  although  less 
than  that  of  the  first.  In  tolerance,  then,  the  tissues  become  indifferent  to 
the  poison;  in  immunity  they  form  an  antitoxin.  Antiricin  is  antagonistic 
only  to  ricin  ;  it  does  not  protect  an  animal  from  any  other  toxalbumin. 

Ricin  and  antiricin  are  not  used  in  therapeutics,  but  ricin  has  repeatedly 
given  rise  to  poisoning,  from  the  beans  being  taken  as  a  substitute  for  the 
oil.  Cattle  have  also  been  poisoned  by  being  fed  on  the  refuse  of  castor  oil 
beans  after  the  oil  had  been  expressed. 

Another  vegetable  toxalbumin  which  resembles  ricin  very  closely  in  its 
effects  is  Abrin,  which  is  obtained  from  the  seeds  of  Abrus  precatorius  or  je- 
quirity,  the  familiar  scarlet  and  black  beans,  which  are  often  formed  into 
necklaces.  Abrin  contains  two  poisons,  a  globulin  and  an  albumose,  of 
which  the  former  is  the  more  powerful.  It  induces  the  same  symptoms 
as  ricin,  but  is  less  poisonous,  and  immunity  can  be  acquired  in  the  same 
way.  Animals  which  are  immune  to  ricin  are  not  more  resistant  to  the  ac- 
tion of  abrin  than  others,  because  the  two  poisons  form  different  antitoxins. 
Abrin  or  jequirity  has  been  used  as  an  irritant  to  the  eye  in  cases  of  granu- 
lar lids  and  of  corneal  opacities.  It  causes  an  acute  inflammation  which 
improves  the  condition  in  some  cases,  but  it  must  be  regarded  as  an  exceed- 
ingly dangerous  remedy,  as  the  inflammation  is  entirely  beyond  the  control 
of  the  surgeons.  In  animals  the  eye  is  often  completely  destroyed  by  the 
application  of  abrin,  while  in  other  experiments  enough  of  the  drug  is  ab- 
sorbed to  cause  fatal  poisoning. 

Crotin  is  another  toxalbumin,  which  is  found  in  the  Croton  Tiglium,  but 
which  does  not  pass  into  croton  oil.  It  is  less  poisonous  than  ricin  and  ab- 
rin, but  resembles  them  in  most  other  points,  except  that  it  does  not  cause 
agglutination  of  the  blood  cells  of  certain  animals,  while  ricin  and  abrin 
have  this  effect  in  all  kinds  of  blood  hitherto  examined.  Many  other  plants 
contain  toxalbumins,  but  none  of  them  have  aroused  so  much  interest  as 
those  mentioned  above. 

Many  animals  produce  proteid  poisons,  such  as  the  snakes,  the  poisonous 
lizard,  Heloderma  suspectum  (Gila  monster),  several  amphibia  and  fish,  and 
the  scorpions  and  spiders  (tarantula).  On  the  other  hand,  several  insect 
poisons  which  resemble  these  poisons  in  their  irritant  action  and  in  some 
other  points,  have  been  shown  not  to  be  proteids.  An  antitoxin  for  snake 
poison  has  been  introduced  recently  under  the  name  of  antivenin,  and  is 
found  in  the  bile  of  poisonous  snakes  and  in  smaller  quantities  in  that  of 
other  animals.  These  animal  poisons  and  the  bacterial  poisons,  however, 
can  be  treated  of  with  advantage  only  in  special  text-books. 

BIBLIOGRAPHY  of  Kicin,  Abrin  and  Crotin. 

Stillmark.     Arb.  a.  d.  pharm.  Instit.  zu  Dorpat,  iii.,  p.  59. 
Martin.     Proc.  Koy.  Soc.,  xlii.,  p.  331  ;  xlvi.,  p.  94. 
Hellin.     Inaug.  Diss.,  Dorpat,  1891. 
Ehrlich.     Deutsch.  med.  Woch. ,  1891,  Nos.  32  and  44. 
Flexner.     Journ.  of  Exp.  Med.,  ii.,  p.  197. 
El/strand.     Robert's  Gorbersdorfer  Veroffentlichungen,  i.,  p.  1. 
Midler.     Arch.  f.  exp.  Path.  u.  Pharm.,  xlii.,  p.  302. 
Jacoby.     Ibid.,  xlvi.,  p.  28  ;  Beitrage  z.  Chem.  Phys.  u.  Path.,  i.,  p.  51. 
46 


722  FERMENTS,   SECRETIONS  AND  TOXALBUMINS. 

V.     COD-LIVER    OIL. 

Cod-liver  oil  has  been  long  used  by  the  fishermen  of  the  North  Sea 
as  a  remedy  in  children's  diseases,  and  was  introduced  into  medicine 
in  the  beginning  of  last  century,  but  became  generally  used  only  in 
the  last  fifty  years. 

It  is  obtained  from  the  liver  of  the  cod-fish  (Gadus  morrhua),  and 
probably  from  other  members  of  the  genus.  Formerly  the  livers  were 
left  to  decompose,  and  the  oil  set  free  by  the  breaking  up  of  the  cells 
was  collected.  It  had  a  most  disagreeable  odor  and  taste,  however, 
and  many  patients  could  not  be  induced  to  take  it,  while  those  who 
were  courageous  enough  to  swallow  it,  often  suffered  from  eructation 
and  diarrhoea  afterwards.  This  method  was  therefore  soon  replaced 
by  the  "  steam-process,"  in  which  the  oil  is  melted  out  of  the  fresh 
livers,  yielding  an  oil  of  much  lighter  color,  and  with  much  less  dis- 
agreeable smell  and  taste.  Quite  recently  a  new  process  has  been  intro- 
duced, by  which  the  oil  is  extracted  by  steam,  without  being  exposed 
to  the  air,  and  it  is  stated  that  oil  thus  obtained  is  less  disagreeable 
than  any  other. 

The  cod-liver  oils  used  in  therapeutics  differ  considerably  in  appear- 
ance and  in  composition,  the  older  preparations  being  brownish  in 
color,  and  having  a  strong  fishy  odor  and  a  somewhat  acrid,  disagree- 
able taste,  while  the  oil  prepared  by  the  more  recent  process  is  pale 
yellow  in  color,  and  has  much  less  odor  and  a  bland  taste. 

Cod-liver  oil  probably  contains  the  ordinary  constituents  of  an  ani- 
mal fat,  olein,  stearin  and  palmitin,  but  the  relative  proportion  in 
which  these  are  present  is  unknown.  Some  free  fatty  acid  is  gener- 
ally found  in  it,  the  darker  preparations  containing  some  4-7  per  cent., 
the  pale  yellow  oil  less  than  one  per  cent,  as  a  general  rule. 

Iodine  and  bromine  are  present  in  traces,  apparently  very  much  smaller 
in  amount  than  is  generally  believed.  The  usual  statement  is  that  0.03- 
0.04  per  cent,  of  iodine  and  0.003-0.005  of  bromine  exists  in  the  oil,  but  some 
oils  have  been  found  to  contain  only  about  one-hundredth  of  this  amount  of 
iodine. 

Phosphorus  is  found  in  traces  in  some  oils,  in  an  organic  combination, 
not  in  the  free  state.  A  small  percentage  of  cholesterin  is  often,  not  invari- 
ably present,  and  bile  acids  and  pigments  have  been  said  to  occur,  but  this 
seems  incorrect.  A  number  of  bases  have  been  found  in  ood-liver  oil  by 
Gautier,  especially  in  the  darker  colored  varieties,  while  the  pale  yellow 
oil  contains  little  or  none.  These  bases  or  alkaloids  (leucomaines)  are 
Butylamine  (C4HUN),  Amylamine  (C5H13N),  Hexylamine  (C6H15N),  Dihy- 
drolutidine  (C7HUN)  and  two  new  non-volatile  ones,  Assellne  and  Morrhuine. 
They  were  found  combined  with  morrhuic,  formic,  butyric  and  other  acids. 
Trimethylamine  has  also  been  said  to  occur  in  it. 

Cod-liver  oil  has  no  very  distinct  action  when  taken  in  ordinary 
doses,  while  in  large  quantities  it  has  a  tendency  to  cause  eructation, 
nausea  and  diarrhrea.  Taken  repeatedly,  it  increases  the  weight  and 
strength,  and  improves  the  general  condition.  The  same  effects  are 
obtained  in  healthy  persons  by  the  use  of  good  food  and  fats,  but  deli- 
cate patients  who  are  unable  to  digest  ordinary  animal  fats,  are  able 


COD-LIVER   OIL.  723 

to  take  cod-liver  oil.  Its  effects  are  obviously  those  of  an  easily  as- 
similable food,  and  it  is  not  a  drug  in  the  ordinary  sense  of  the  term, 
and  has  therefore  no  place  in  pharmacology  properly  speaking,  but 
should  be  classed  along  with  other  foods.  It  is  always  treated  of  as 
a  drug,  however,  because  it  has  often  been  supposed  to  have  some  spe- 
cific effect  quite  apart  from  ordinary  foods.  It  is  generally  believed 
to  differ  from  ordinary  fats  in  being  more  readily  assimilable,  but  the 
explanation  of  this  fact  is  by  no  means  agreed  upon,  for  though  it  is 
often  said  to  be  more  rapidly  absorbed  from  the  intestine,  there  is  lit- 
tle reliable  evidence  that  such  is  the  case.  A  few  experiments  have 
been  carried  out,  but  by  no  means  enough  to  establish  the  truth  of  the 
statement  satisfactorily,  and  the  chief  argument  brought  forward  in 
its  support  is  that  cod-liver  oil  forms  an  emulsion  in  the  test-tube 
more  rapidly  than  other  oils.  It  is  undoubtedly  well  borne  by  the 
stomach,  but  it  has  not  been  often  compared  with  other  oils  in  regard 
to  this  point,  and  it  is  still  impossible  to  state  that  other  oils  adminis- 
tered with  the  same  care  as  cod-liver  oil  are  not  equally  successful 
remedies. 

Buchheim  explained  that  cod-liver  oil  formed  an  emulsion  rapidly 
on  account  of  the  free  acid  it  contained,  and  this  has  generally  been 
put  forward  as  accounting  for  its  effects  in  therapeutics.  As  far  as 
regards  the  old  dark-colored  oils,  this  explanation  may  hold  good,  but 
the  pale  oil  now  used  in  therapeutics  often  contains  less  free  acid  than 
ordinary  olive  oil.  Some  enthusiastic  supporters  of  Buchheim's  theory 
have,  therefore,  asserted  that  the  pale  oil  does  not  give  the  same  results 
as  the  older,  less  pure,  acid  preparations,  but  this  is  not  the  general 
opinion  of  the  medical  profession. 

The  older  explanations  started  from  the  view  that  cod-liver  oil  is  a  drug, 
that  the  oil  itself  is  only  a  means  to  administer  certain  active  principles 
contained  in  it.  Thus  iodine  and  phosphorus  were  in  turn  supposed  to  be 
the  essential  constituents,  but  have  both  been  shown  to  be  present  in  too 
small  quantities  to  be  of  any  effect.  More  recently  cholesterin  has  been 
suggested  as  the  curative  agent,  but  it  is  present  in  smaller  quantities  in 
cod-liver  oil  than  in  many  other  foods. 

Lastly  the  bases  have  been  credited  with  lending  cod-liver  oil  all  its  vir- 
tues. But  the  pale  oil  contains  only  traces  of  these,  and  again  the  state- 
ment has  been  made  that  the  brown  oil  is  superior.  An  attempt  has  been 
made  to  support  this  theory  by  examining  the  urine  of  persons  under  treat- 
ment with  the  bases  separated  from  the  oil.  The  urine  has  been  found  in- 
creased in  amount,  the  urea  augmented,  the  less  oxidized  forms  of  nitrogen 
diminished,  but  these  experiments  are  of  no  value,  because  apparently  no 
measures  were  taken  to  keep  the  amount  of  food  ingested  constant. 

Several  substitutes  for  cod-liver  oil  have  been  proposed,  such  as  Lipanin 
(v.  Mering),  which  is  formed  from  olive  oil  by  the  addition  of  6  per  cent,  of 
oleic  acid,  and  which  was  suggested  by  the  theory  that  cod-liver  oil  owes  its 
rapid  absorption  to  the  presence  of  free  acid.  A  mixture  of  cacao  butter 
and  oleic  acid  has  also  been  introduced,  as  well  as  oil  of  sesame  and  olive 
oil.  On  the  theory  that  the  bases  were  the  indispensable  part  of  the  oil, 
Morrhuol,  a  crude  mixture  of  bases,  acids  and  pigment,  has  been  introduced 
into  therapeutics  and  used  to  some  extent,  but  it  has  not  proved  a  substitute 
for  the  oil  in  practice.  Lipanin  has  been  used  only  to  a  limited  extent,  and 
has  not  been  able  to  supplant  cod-liver  oil,  although,  like  oil  of  sesanus  and 


724  FERMENTS,   SECRETIONS  AND   TOXALBUMINS. 

olive  oil,  it  has  the  advantage  of  being  much  less  disagreeable  in  smell  and 
taste.  This  may  perhaps  be  due  to  the  conservatism  of  the  medical  profes- 
sion, rather  than  to  the  special  merits  of  cod-liver  oil. 

On  the  whole,  cod-liver  oil  has  not  been  shown  to  have  any  action 
apart  from  that  of  an  easily  digested  food,  and  its  superiority  to  some 
other  fats  and  oils  has  not  been  satisfactorily  established. 

PREPARATION. 

OLEUM  MORRHTJ^E  (U.  S.  P.,  B.  P.),  cod-liver  oil,  Oleum  Jecoris  Aselli, 
a  fixed  oil  obtained  from  the  fresh  livers  of  Gadus  Morrhua  and  of  other 
species  of  Gadus,— a  pale  yellow,  thin,  oily  liquid,  with  a  peculiar,  slightly 
fishy,  but  not  rancid  odor,  and  a  bland  slightly  fishy  taste.  4-16  c.c.  (1-4 
fl.  drs.). 

Emulsum  Olei  Morrhuce  (U.  S.  P.),  50  per  cent.  8  c.c.  (2  fl.  drs.). 

Emulsum  Olei  Morrhuce  cum  Hypophosphitibus  (U.  S.  P.),  50  per  cent,  cod-liver 
oil.  8  c.c.  (2fl.  drs.). 

Therapeutic  Uses.  —  Cod-liver  oil  is  used  in  chronic  wasting  diseases, 
such  as  tuberculosis,  scrofula,  rickets  and  some  forms  of  syphilis.  It 
is  especially  beneficial  in  the  earlier  stages  of  pulmonary  phthisis,  but 
has  no  specific  virtues  here  or  elsewhere  apart  from  those  of  an  easily 
digested  fat.  In  all  forms  of  malnutrition  and  delicacy  in  children,  it 
is  largely  used,  and  undoubtedly  causes  a  considerable  increase  in 
weight,  but  care  must  be  taken  that  it  does  not  disturb  the  digestion, 
especially  if  the  darker  oils  are  used.  In  some  persons  pure  cod-liver 
oil  always  induces  nausea,  but  a  much  larger  number  refuse  to  take 
the  brown  oil.  In  most  cases  the  light-colored  oil  is  taken  readily, 
especially  if  the  dose  be  small  at  first  (a  teaspoonful).  When  there  is 
dyspepsia  or  a  tendency  to  diarrhoea,  cod-liver  oil  should  be  given 
with  caution,  and  it  is  generally  prescribed  only  in  cold  weather, 
as  it  is  found  that  patients  have  a  distaste  for  it  in  summer.  When 
fever  or  acute  disease  is  present,  cod-liver  oil  is  generally  found  of 
little  value,  perhaps  on  account  of  the  disturbed  condition  of  the 
digestion.  Cod-liver  oil  should  not  be  forced  on  patients ;  when  it 
continues  to  induce  nausea  and  eructation  after  a  fair  trial,  it  should 
be  abandoned. 

Innumerable  means  have  been  proposed  to  conceal  the  odor  and 
taste,  but  it  is  generally  conceded  that  when  possible  the  pure  oil  is 
better  given  alone.  When  patients  cannot  be  induced  to  take  it  in 
this  way,  some  volatile  oil,  ether,  or  brandy  may  be  added  to  it; 
saccharine  has  also  been  used  to  sweeten  it.  Creosote  is  sometimes 
mixed  with  cod-liver  oil  in  cases  of  phthisis,  or  an  emulsion  is  formed 
containing  cod-liver  oil,  some  flavoring  substance,  iron,  hypophos- 
phites  or  calcium.  Extract  of  malt  and  cod-liver  oil  form  a  common 
mixture,  and  are  the  basis  of  many  patented  emulsions. 

In  general,  the  pale  oil  is  preferred,  but  it  must  be  added  that  some 
physicians  persist  in  the  use  of  the  darker  forms,  which  contain  more 
bases  and  more  free  acid,  but  have  a  much  more  disagreeable  taste  and 
smell,  and  are  more  liable  to  disturb  the  digestion.  Of  the  substitutes 
for  cod-liver  oil,  lipanin  has  little  taste  and  is  generally  taken  readily. 


PHLOEIDZIN.  725 

It  may  be  given  shaken  up  in  inilk  or  formed  into  an  emulsion.    Olive 
oil  is  equally  valuable  and  is  generally  considered  more  palatable. 

BIBLIOGRAPHY. 

Naumann.     Arch,  der  Heilkunde,  1865,  p.  536. 

Buchheim.     Arch.  f.  exp.  Path.  u.  Pharm.,  iii.,  p.  118. 

V.  Merino.     Therap.  Monatsh.,  1888,  pp.  49  and  233. 

Salk&wsfd.     Ibid.,  1888,  p.  230. 

Hauser.     Ztschr.  f.  klin.  Med.,  xiv.,  p.  543  ;  xx.,  p.  239. 

Lowenthai.     Arch.  f.  Anat.  u.  Phys.,  1897,  p.  258. 

Mersereau.     New  York  Med.  Journ.,  1899,  ii.,  p.  11. 

Sternberg.     Ztschr.  f.  klin.  Med.,  xxii.,  p.  295. 

Bouillot.     Compt.  Kend.  de  1'Acad.  des  Scien.,  cxv.,  p.  754. 

Gautier  et  Mourgues.     Les  Alcaloides  de  Huile  des  Foies  de  Morue,  Paris,  1890. 

Heyerdahl.    F.  Pekel  Molar's  Cod-liver  Oil  and  Chemistry,  London,  1895,  p.  88. 

WeUs.     Brit.  Med.  Journ.,  Oct.  18,  1902. 

VI.    PHLORIDZIN.1 

Phloridzin  is  not  used  in  therapeutics,  but  has  attracted  some  attention 
from  its  effects  in  animals,  and  may  therefore  be  mentioned  shortly.  It  is 
a  glucoside  (C21H24O10  +  2H2O)  found  in  the  rootbark  of  the  apple,  pear, 
cherry  and  plum  tree.  When  given  in  large  quantities  by  the  mouth  it 
sometimes  causes  some  diarrhoea  in  animals,  but  apart  from  this  its  only 
effect  is  glycosuria,  which  also  follows  its  injection  subcutaneously  or  intra- 
venously. The  urine  is  found  to  contain  5-15  per  cent,  or  even  more  of 
sugar,  sometimes  along  with  acetone  and  oxybutyric  acid,  so  that  the  intox- 
ication seems  at  first  sight  to  resemble  diabetes  mellitus  in  man  very  closely. 
Phloridzin  induces  the  same  results  in  man,  and  the  glycosuria  is  not  accom- 
panied by  any  other  symptoms  generally.  It  differs  from  true  diabetes, 
however,  in  the  fact  that  the  sugar  of  the  blood  is  not  increased  in  amount. 
The  glycosuria  is  not  due  to  any  change  in  the  general  metabolism  of  the 
body,  therefore,  but  to  some  alteration  of  the  renal  epithelium,  by  which 
the  blood  sugar  escapes  into  the  urine  instead  of  being  retained  in  the  body 
and  used  as  a  source  of  energy.  This  has  been  definitely  proven  by  Zuntz, 
who  showed  that  when  phloridzin  was  injected  into  one  renal  artery,  the 
urine  secreted  by  the  corresponding  kidney  contained  sugar,  while  that  from 
the  other  remained  normal  for  some  time.  As  the  available  sugar  is  drained 
off*  in  the  urine,  the  tissues  rapidly  manufacture  more  and  pour  it  into  the 
blood.  As  long  as  sufficient  food  is  given,  the  loss  of  sugar  does  not  seem  to 
entail  any  increase  in  the  destruction  of  the  proteid  tissues,  but  when  phlo- 
ridzin is  given  to  starving  dogs,  the  waste  of  sugar  has  to  be  made  up  from 
the  tissues,  and  the  nitrogen  of  the  urine  accordingly  rises  in  amount,  while 
at  the  same  time  the  liver  cells  become  infiltrated  with  fat  globules.  The 
statement  that  the  sugar  of  the  milk  is  increased  by  phloridzin  has  proved 
to  be  incorrect. 

Glycosuria  may  be  maintained  for  an  indefinite  time  if  the  administration 
of  phloridzin  be  continued,  and  animals  recover  rapidly  when  the  treatment 
is  stopped.  The  glucoside  is  probably  excreted  in  the  urine  unchanged, 
although  this  has  not  been  quite  satisfactorily  demonstrated  as  yet.  Phlo- 
ridzin may  be  decomposed  into  a  sugar,  phlorose,  and  phloretin,  which  also 
induces  glycosuria. 

Syzygium  Jambolanum,  or  Jambul,  a  tree  growing  in  South  America  and 
in  the  East  Indies,  is  said  to  contain  some  unknown  substance  which  has  a  spe- 
cific action  in  diabetes.  Several  clinical  observers  have  noted  improvement 
in  some  cases,  but  others  have  seen  no  result  whatever  follow,  and  as  a  general 

1  Phloridzin  is  not  in  any  way  related  to  the  other  drugs  of  this  part,  and  has  only 
been  inserted  here  because  no  suitable  position  could  be  found  elsewhere. 


726  FERMENTS,    SECRETIONS  AND  TOXALBUM1NS. 

rule  no  sufficient  estimation  of  the  sugar  of  the  urine  was  made  in  the  cases  in 
which  the  treatment  was  believed  to  be  successful.  Some  experiments  on 
animals  seem  to  indicate  that  it  modifies  the  sugar  formation  in  the  tissues, 
but  cannot  be  accepted  until  they  are  confirmed  by  further  research. 

BIBLIOGRAPHY  of  Phloridzin. 

V.  Mering.     Zts.  f.  klin.  Med.,  xiv.,  p.  405  ;  xvi.,  p.  431. 
Rosenfeld.     Ibid.,  xxviii.,  p.  256. 

Zuntz.     Arch.  f.  Anat.  u.  Phys.  (Phys.  Abth.),  1895,  p.  570. 
Coolen.     Arch,  de  Pharmacodynam.,  i.,  p.  267  ;  ii.,  p.  255. 

Kulz,  Wright,  Moritz,  Prausnitz,  Cremer,  Hitter,  Lusk.     Zts.  f.  Biol.,  xxvii.,  xxviii., 
xxix.,  xxxvi. 

Reilly,  Nolan  and  Lusk.     Am.  Jour,  of  Phys.,  i.,  p.  395. 
Levene.     Jour,  of  Exp.  Med. ,  ii. ,  p.  107. 
Pappenheim.     Arch.  f.  Verdauungskrank.,  iii.,  p.  421. 
Imdebrandt.     Virchow's  Arch.,  cxxxi.,  p.  26. 
Pavy,  Brodie  and  Siau.     Journ.  of  Phys.,  xxix.,  p.  467. 
LoewL     Arch.  f.  exp.  Path.  u.  Pharra.,  1.,  p.  326. 


PART  VI. 

MENSTRUA  AND   MECHANICAL  REMEDIES. 

Oleum  Theobromatis  (U.  S.  P.,  B.  P.),  cacao-butter,  a  fixed  oil  expressed 
from  the  seeds  of  Theobroma  cacao,  forms  a  yellowish-white  solid  having  a 
faint,  agreeable  odor  and  a  bland,  chocolate  taste.  It  melts  a  little  below 
the  temperature  of  the  body.  Cacao-butter  is  used  almost  exclusively  to 
form  suppositories,  in  which  astringents  and  other  remedies  are  incorporated. 
When  these  are  introduced  into  the  rectum,  they  melt  and  the  active  prin- 
ciple is  liberated. 

Keratin  (not  official)  is  a  substance  obtained  from  horns,  hoofs,  nails,  etc., 
which  is  insoluble  in  the  gastric  juices,  but  is  dissolved  by  the  alkaline  pan- 
creatic secretion.  It  is  used  to  coat  pills  which  it  is  desired  to  protect  from 
disintegration  in  the  stomach. 

Kaolinum  (B.  P.,  U.  S.  P.),  or  porcelain  clay,  is  used  in  the  formation  of 
pills  containing  easily  reduced  bodies,  such  as  silver  nitrate  or  potassium  per- 
manganate. Mixed  with  the  ordinary  vegetable  excipients,  such  as  confection 
of  roses,  or  extract  of  liquorice  or  gentian,  these  salts  would  be  reduced  at  once. 
Kaolin  is  an  aluminium  silicate  and  forms  a  soft  whitish  powder  insoluble  in 
water  or  dilute  acids. 

Gataplasma  Kaolin!  (U.  S.  P.),  kaolin  moistened  with  glycerin  and  applied 
as  a  poultice. 

Sapo  (U.  S.  P.),  Sapo  Duras  (B.  P.),  hard  soap,  white  Castile  soap,  is  pre- 
pared from  soda  and  olive  oil. 

Sapo  Mollis  (U.  S.  P.,  B.  P.),  soft  soap,  sapo  viridis,  a  soap  made  from 
potash  and  olive  oil. 

Sapo  Animalis  (B.  P.),  curd  soap,  soap  made  with  sodium  hydroxide  and 
a  purified  animal  fat  consisting  chiefly  of  stearin  ;  it  contains  about  30  per 
cent,  of  water. 

These  soaps  are  used  in  therapeutics  as  ingredients  of  liniments  and  plas- 
ters. Water  containing  soap  is  often  thrown  into  the  rectum  as  an  enema, 
and  in  infants  a  soapstick  inserted  into  the  anus  generally  provokes  evacua- 
tion of  the  bowels  in  a  few  minutes. 

Soaps  impregnated  with  antiseptics,  such  as  perchloride  of  mercury,  car- 
bolic acid,  tar,  or  iodine,  are  often  used  to  disinfect  the  hands. 

The  chief  preparations  in  which  soap  is  used  in  the  pharmacopoeias  are  : 

Emplastrum  Saponis  (U.  S.  P.,  B.  P.),  soap  plaster. 

Linimentum  Saponis  (U.  S.  P.,  B.  P.),  soap  liniment. 

Linimentum  Saponis  Mollis  (U.  S.  P.,  B.  P.). 

The  liniments  consist  of  alcohol  with  soap  in  suspension,  perfumed  with 
volatile  oils,  and  are  mildly  irritant  to  the  skin.  They  are  used  largely  as 
bases  for  other  liniments. 

The  use  of  the  oils,  fats  and  glycerin  as  vehicles  for  the  application  of 
remedies  to  the  skin  has  been  mentioned  already  (page  49).  They  may  also 
be  used  to  dissolve  remedies  which  are  insoluble  in  water,  but  which  are  to 
be  given  by  the  mouth,  such  as  phosphorus  (in  oil). 

Wax  (cera  alba,  cera  flava)  is  used  chiefly  to  increase  the  consistency  of 
ointments.  A  special  series  of  preparations  somewhat  stifFer  than  the  oint- 
ments are  the  cerates  of  the  U.  S.  P. 

Plasters  are  sticky  adhesive  substances  which  are  chiefly  used  to  give  me- 
chanical support,  but  which  are  often  impregnated  with  active  remedies  in 
order  to  elicit  their  local  action  on  the  skin.  The  basis  of  many  of  the  plas- 

727 


728  MENSTRUA   AND  MECHANICAL  REMEDIES. 

ters  is  lead  plaster,  which  is  obtained  by  the  action  of  lead  oxide  on  olive  oil 
and  consists  for  the  most  part  of  lead  oleate. 

Emplastrum  Plumbi  (U.  S.  P.,  B.  P.),  lead  or  diachylon  plaster. 

Emplastrum  Adhcesivum  (U.  S.  P.),  Resince  (B.  P.),  adhesive  plaster. 

Emplastrum  Saponis  (U.  S.  P.,  B.  P.),  soap  plaster. 

Emplastrum  Opii  (U.  S.  P.,  B.  P.),  opium  plaster. 

Emplastrum  Belladonna  (U.  S.  P.,  B.  P.),  belladonna  plaster. 

Emplastrum  Picis  (B.  P.),  Burgundy  pitch  plaster. 

Emplastrum  Capsici  (U.  S.  P.). 

Emplastrum  Calefaciens  (B.  P.),  warming  plaster. 

Emplastrum  Cantharidis  (B.  P.). 

Emplastrum  Hydrargyri  (IT.  S.  P.,  B.  P.),  mercury  plaster. 

Emplastrum  Ammoniaci  cum  Hydrargyro  (B.  P.). 

Emplastrum  Plumbi  lodidi  (B.  P.). 

Emplastrum  Menthol  (B.  P.). 

Court  plaster  is  formed  from  isinglass,  the  dried  swimming  bladder  of  sev- 
eral species  of  sturgeon,  which  is  dissolved  in  water,  alcohol  and  glyeerin 
and  painted  on  taffeta.  Isinglass  differs  from  lead  plaster  and  its  deriva- 
tives in  being  transparent,  so  that  if  it  be  spread  on  a  flesh-colored  cloth,  it 
disfigures  the  hands  and  face  less  than  the  others. 

Lead  plaster,  resin  plaster  and  isinglass  plaster  are  used  only  to  cover  and 
protect  cuts  and  abrasions,  and  to  keep  the  edges  of  wounds  in  apposition. 
The  adhesive  plaster  and  isinglass  plaster  are  superior  to  lead  plaster,  as  they 
stick  more  firmly.  It  is  perhaps  unnecessary  to  add  that  plasters  are  alwrays 
applied  spread  on  cloth.  Opium  and  belladonna  plasters  are  believed  to 
lessen  pain  locally  as  well  as  to  give  support,  but  this  is  perhaps  imaginary. 
Belladonna  plaster  is  said  to  lessen  the  secretion  of  perspiration  and  of  milk. 
The  pitch,  arnica,  menthol  and  capsicum  plasters  have  some  irritant  action 
and  this  is  of  course  more  marked  in  the  case  of  the  warming  plaster  and 
cantharides  plaster.  Some  mercury  is  absorbed  when  the  mercury  plasters 
are  applied  to  the  skin,  but  this  method  of  administration  allows  of  even  less 
accurate  dosage  than  inunction,  and  is  seldom  used.  Iron  plaster  is  devoid 
of  any  properties  apart  from  those  shared  with  the  others. 

Another  series  resembling  the  plasters  in  their  sphere  of  usefulness  is 
formed  by  the  Collodia.  Their  basis  is  pyroxylin,  or  soluble  gun-cotton, 
which  is  formed  from  cotton  by  the  action  of  sulphuric  and  nitric  acids,  and 
which  consists  of  a  mixture  of  nitrates  of  cellulose.  Collodion  is  formed  by 
dissolving  pyroxylin  in  a  mixture  of  alcohol  and  ether.  When  these  evapo- 
rate, there  remains  a  fine  layer  of  pyroxylin,  which  protects  the  surface  to 
which  it  is  applied  and  gums  the  edges  of  slight  cuts  together.  This  collodion 
is  rendered  less  brittle  by  the  addition  of  Canada  turpentine  and  castor  oil  in 
small  proportions,  and  is  then  known  as  flexible  collodion.  A  blistering 
collodion  is  formed  by  the  addition  of  powdered  cantharides  to  the  flexible 
preparation.  Another  preparation  contains  tannic  acid. 

Pyroxylinum  (U.  S.  P.,  B.  P.),  soluble  gun  cotton,  colloxylin. 

Collodium  (U.  S.  P.,  B.  P.),  collodion. 

Collodium  Flexile  (U.  S.  P.,  B.  P.),  flexible  collodion. 

Collodium  Cantharidatum  (U.  S.  P.),  Collodium  Vesicans  (B.  P.),  blistering 
collodion. 

Collodium  Stypticum  contains  20  per  cent,  of  tannic  acid. 

Instead  of  collodion,  india-rubber,  Caoutchouc  (B.  P.),  Elastica  (U.  S.  P.), 
may  be  dissolved  in  chloroform  and  applied  in  the  same  way. 

Calcii  /Sulphas  Exsiccatus  (U.  S.  P.),  Dried  Gypsum,  used  to  impregnate 
bandages,  which  then  become  hard  and  immovable. 


CLASSIFICATION  OF  DRUGS   ACCORDING  TO 
THEIR  THERAPEUTIC  USE. 


I.  Drugs  applied  for  their  local  action 
to  the  skin,  wounds,  or  visible 
mucous  membranes. 

Corrosives  or  caustics. 
Potash,  540 
Mercury  nitrate,  650 
Potassium  and  sodium  carbonate, 

540 

Silver  nitrate,  686 
Zinc  chloride,  684 
Nitric  acid  and  other  acids,  555 
Chromic  acid,  699 
Burnt  alum,  695 
Bromine,  582 
Arsenic,  603 
Lead  nitrate,  670 
Trichloracetic  acid,  563 
Ammoniated  mercury  and  other 

mercury  preparations,  650 
(Soda,  540) 

(Sodium  ethylate,  545) 
(Lime,  564) 
(Carbolic  acid,  393) 

Disinfectants  and  antiseptics. 

Hydrogen  peroxide,  587 

Permanganate  of  potassium,  589 

Chlorine,  582 

Sulphurous  anhy- 
dride, 562 

Formaldehyde,  423 

Carbolic  acid,  393 

Corrosive    sublimate    and    other 
mercury  salts,  650 

Silver  nitrate,  686 

Zinc  chloride,  684 

Boracic  acid,  578 

lodoform,  lodol,  517 

Cresol,  399 

Tar,  405 

Salicylic  acid,  408 

(Benzoic  acid,  419) 

(Camphor,  426) 

(Sulphites,  529) 

(Sulphocarbolates,  417) 

(Volatile  oils  (thymol,  eucalyptol, 
etc.)) 

Astringents. 

Tannic  acid  series,  109 
Iron  preparations,  e.  g.,  sulphate, 
655 


not  applied 
to  living 
objects. 


II. 


Bismuth  preparations,  692 
Lead  acetate,  670 
Zinc  sulphate  and  oxide,  683 
Copper  sulphate,  680 
Alum,  695 

Styptics. 

Soluble  astringents  (see  above). 
Iron  perchloride,  655 
Silver  nitrate,  686 
Burnt  alum,  695 

To  contract  vessels  and  reduce  hemorrhage 

and  swelling. 
Cocaine,  298 
Suprarenal    extract    (adrenalin), 

458 

Emollients  or  protectives. 
Emollients,  49 
Plasters  and  Collodia,  728 
Dusting-powders—starch,  talcum, 
chalk,  and  many  insoluble  me- 
tallic powders,  which  may  also 
be  slightly  astringent,  53. 

Local  anodynes  and  analgesics  for  pain 
and  itching. 

Bicarbonate  of  potassium,  541 
Cocaine,  Eucaine,  Orthoform,  etc., 

298 

Carbolic  acid,  393 
Chloretone,  186 

Prussic  acid,  238) 

Atropine,  276) 

Aconite,  328) 

Veratrine,  388) 

Local  anaesthetics. 

Cold  by  evaporation  of  ether,  etc., 

181 
Cocaine  and  Eucaine,  298 

Drugs  used  for  affections  of  the 
alimentary  tract. 

MOUTH  AND  THROAT  (see  Section  I.). 
Demulcents,  45 

Chlorates,  522 
Ammonium  chloride,  496 
Cubebs,  75 


To  lessen  salivation. 
Atropine,  276 


729 


730 


THERAPEUTIC  CLASSIFICATION. 


Flavoring  substances. 
Sugars,  54 


66 


eugars,  01 
Volatile  oil  series, 
Acids  (citric),  554 
Syrup  of  Tolu,  Ginger,  etc. 

STOMACH. 


Pepsin,  Papain,  etc.,  705 
Hydrochloric  acid,  561 

Emetics. 

Common  salt,  486 
Mustard,  88 
Warm  water. 
Apomorphine,  234 
Ipecacuanha,  339 
Tartar  emetic,  629 
Copper  sulphate,  682 
Zinc  sulphate,  686 
(Alum,  696) 
(Ammonium  carbonate,  551) 

To  lessen  irritation  and  vomiting. 
Opium,  206 
Chloral,  186 
Lime-water,  565 
Bismuth,  692 
Cerium  oxalate,  695 
Cold  (ice). 
Cocaine,  298 
Carbonic-acid  water,  580 
Demulcents,  45 
(Prussic  acid,  238) 

To  lessen  acidity,  antacid's. 

Potassium  and  Sodium  car- 
bonate and  Bicarbonates, 
540 

Magnesia  and  Magnesium  car- 
bonate, 540 

Lime-water  and  chalk,  565 

Lithium  carbonate,  540 

To  increase  secretion,  bitters. 
Simple  bitters,  56 
Nux  vomica,  Strychnine,  195 
Cinchona  and  Quinine,  353 
(Hydrastis,  229) 
(Salicin,  413) 

Carminatives. 

Volatile  oil  carminatives,  61 
Alcoholic  preparations. 
Carbonic  acid  waters,  580 
Carbonates  and  Bicarbonates, 

540 

Bitters  (see  above). 
Camphor,  426 
Charcoal,  577 

Ammonium  carbonate,  540 
(Peppers,  72) 

INTESTINE. 

To  promote  digestion. 
(Pancreatin,  706) 
(Diastase,  707) 


To  promote  evacuation — purgatives. 
Vegetable  purgatives,  93 
Saline  cathartics,  530 
Mercurial    purgatives — Calo- 
mel and  Metallic  prepara- 
tions, 634 
Sulphur,  573 
Enemata. 

Glycerin  suppositories,  51 
(Atropine). 

To  lessen  movement  and  relax  spasm. 
Opium  and  Morphine,  206 
Tannic  acid  series,  109 
Lime-water,  565 
Lead  acetate,  670 
Bismuth,  692 
Atropine    (to   relax   spasm), 

276 
(Alum,  695) 

To  destroy  parasites — anthelmintics. 
Male  fern,  116 
Pomegranate,  119 
Cusso,  etc.,  118 
Santonin,  120 
Calomel,  634 
Salol,  408 

(Some  volatile  oils). 
(Chloroform,  178) 
(Thymol,  Naphtol,  400) 
(Quassia  enema,  56) 

Disinfectants  and  antiseptics. 

(Vegetable  and  Saline  purga- 
tive s). 

Mercurial  purges — Calomel, 
634 

Naphtol,  403 

Salol,  408 

III.  Drugs  used  for  their  effects  on 
the  circulation. 

HEART. 

To  strengthen  contraction. 
Digitalis  group,  435 
To  accelerate  pulse. 

Atropine,  276 
(Camphor,  426) 
(Caffeine,  244) 

To  slow  the  pulse. 

Digitalis  group,  435 
Aconite,  328 
Veratrine,  334 
Strychnine,  195 

VESSELS. 

To  contract  calibre  and  raise  blood- 
pressure. 

Digitalis,  435 
Strychnine,  195 
Caffeine,  244 
Camphor,  426 
Ergot,  472 


THERAPEUTIC  CLASSIFICATION. 


731 


To  relax  vessels  and  lower  blood- 
pressure. 
Nitrite  series,  464 

To    arrest     internal     hemorrhage 

(styptics). 
Ergot,  472 
Hydrastine  and  Hydrasti- 

nine,  229 
Opium     and    Morphine    (to 

allay  restlessness). 

To  remove  fluid  (dropsy,  anasarca). 
Digitalis  series,  435 
Diuretics    (see    Kidney  ,  be- 
low). 

Saline  cathartics,  530 
Diaphoretics  (see    Skin,   be- 
low). 

(Vegetable  cathartics,  93) 
(Salicylic  acid,  408) 

IV.   Drugs  used  for  their  effects  on 
the  genito-urinary  system. 

To  increase  the  flow  of  urine  (diuretics), 
Caffeine  and  Theobromine,  244 
Digitalis  and  Squills,  435 
(Turpentine,      Uva     Ursi,      Sco- 

parms). 
Nitrates,  527 
Acetates,  550 
Citrates,  iodides  of   the  alkalies, 

606 

Carbonates,  540 
Mercury — calomel       and      blue 

pill,  634 

To  render  the  urine  less  acid. 

Alkali   carbonates  and   bicarbon- 

ates,  540 
Acetates,  550 
Citrates,  550 

To  render  the  urine  antiseptic. 
Copaiba  series,  74 
Salol  and  Salicylates,  408 
Sodium  sulphocarbolate,  417 
Borax,  578 
Urotropin,  425 

Local  antiseptics,  astringents,  ano- 
dynes, caustics,  etc.,  are  used  in 
the  urethra  and  bladder. 

To  promote    contraction   of   the    uterus 

(ecbolics). 
Ergot,  472 
Quinine,  353 
(Pilocarpine,  311) 
(Cottonroot-bark,  480) 
(Hydrastis,  229) 

To     promote     menstruation    (emmena- 

gogues). 
Iron,  655 

Vegetable  purgatives— aloes,  93 
(Myrrh). 


V.  Drugs  used  for  their  effects  on  the 

respiratory  system. 

To  stimulate  the  respiratory  centre. 
Atropine,  276 
Caffeine,  244 
Camphor,  426 
Strychine,  195 
(Alcohol  ?). 

To  reduce  the  irritability  of  the  centre  in 

cough. 
Opium,   Morphine,  and  Codeine, 

206 

(Heroine). 
Chloral  series,  186 
Bromides  of  the  alkalies,  500 

To  increase   and   liquefy  the    bronchial 

secretion. 

Ipecacuanha,  339 
Tartar  emetic,  629 
Squills,  435 
Senega,  346 

Ammonium  carbonate,  551 
Iodides  of  the  alkalies,  506 
(Lobelia,  275) 

To  lessen  the  secretion  of  the  bronchi  (f). 
Benzoic      acid,      Benzoin,     Tolu 

Balsam,  419 

Ammonium  chloride,  496 
Cubebs,  73 

To  relax  bronchial  spasm  (f)  in  asthma. 
Belladonna  and  Atropine,  276 
Lobelia,  275 
Nitrite  series,  464 
Iodides,  506 

(Charta  potassii  nitratis,  527) 
(Aspidosperma,  352) 

VI.  Drugs  used  for  their  effects  on  the 

central  nervous  system. 

Stimulants. 

(a)   The  spinal  cord. 
Strychnine,  195 
(6)    The  brain  and  medulla  oblon- 

gata. 

Atropine  (cocaine),  276 
Camphor,  426 
Caffeine,  244 

Depressants. 

(a)  To    paralyze    sensation — Gen- 

eral an/Ksthetics. 
Ether,    Chloroform,   Nitrous 
oxide,  153-186 

(b)  To  induce  sleep  and  rest — hyp- 

notics or  narcotics. 
Opium  and  Morphine,  206 
Alcohol,  129 
Chloral  group,  186 
Bromides,  500 
Hyoscine,  276 
Cannabis  indica,  232 


732 


THERAPEUTIC  CLASSIFICATION. 


To  relieve  pain — analgesics  or  an 


Opium,  206 

Cannabis,  232 

Antipyrine  series.  369 

(Alcohol,  129) 

(Chloral,  186) 

(Arsenic,  Iodides,  Quinine 
Nitrites  are  sometimes  of 
value  in  headache). 

VII.  Drugs  used  to  reduce  fever  tern 

perature. 

Antipyrine  and  Acetanilide group 

369 

Quinine,  353 
Aconite,  328 
Salicylic  acid  group,  408 
Diaphoretics  (see  below). 
(Resorcin,  Guaiacol,  401) 

VIII.  Drugs  used  for  their  effects  on 
the  liver. 

To  increase  the  secretion  of  bile — chola- 

gogues. 
Ox-gall,  708 
(Salicylic  acid,  408) 

IX.  Drugs  used  for  their  effects  on  the 

blood. 

To  increase  the  haemoglobin. 
Iron,  655 
Arsenic,  603 

To  increase  the  alkalinity. 

Alkali  carbonate  group,  540 
Acetates  and  Citrates,  550 

X.  Drugs  used  for  specified  diseases. 

In  malaria. 

Quinine,  353 
Arsenic,  603 

In  syphilis. 

Mercury,  634 
Iodides,  506 

In  rheumatic  fever. 

Salicylates,  Salol,  408 

In  myxoedema  and  some  other  thyroid  dis- 
eases. 
Thyroid  extract,  711 

In  gout. 

(Colchicum,  343) 

XI.  Drugs  used  for  their  effects  on  the 

skin. 

Corrosives  or  caustics,  729 
Emollients  and  protectives,  729 
Local  anodynes  and  anaesthetics,  729 
Irritants. 

Turpentine  oil  group,  86 
Mustard,  88 
Cantharides,  89 
Croton  oil,  97 
Tartar  emetic,629 


Camphor,  426 
Menthol,  426 
Iodine,  513 
Ammonia,  551  • 
(Aconite,  328) 
(Veratrine,  334) 

Disinfectant  or  irritant  ointments  in 
parasitic  skin  diseases. 

Mercury  ointment,  634 

Sulphur  ointment,  573 

Tar,  405 

Ichthyol,  407 

Benzoin,  Storax,  and  Peru  bal- 
sam, 418 

Naphtalin  and  Naphtol,  403 

Resorcin,  401 

Thymol,  400 

Pyrogallol,  402 

Chrysarobin,  102 

Camphor,  426 

Boracic  acid,  578 

lodol  and  other  organic  iodine 
compounds,  517 

Organic  bismuth  preparations, 
695 

Alum  preparations,  697 

Arsenic,  Iodide  of  Potassium,  etc., 
may  be  used  internally  in  skin 
diseases. 

Drugs  administered  internally  to  increase 
the  secretion  of  perspiration  (dia- 
phoretics or  sudorifics). 
Ipecacuanha,  339 

and     other     nauseating    ex- 
pectorants (antimony). 
Ipecacuanha    and    Opium     (Do- 
ver's powder),  339 
Camphor,  426 
Pilocarpine,  311 

Drugs   administered  internally  to  lessen 

secretion  of  perspiration. 
Atropine  and  Belladonna,  276 
Agaricin,  297 
Camphoric  acid,  426 

Drugs  applied   locally  and  internally  to 

arrest  the  secretion  of  milk. 
Atropine. 

XII.    Drugs   used   locally  for   their 
effects  on  the  eye. 

Astringents,  729 
Disinfectants,  729 
Caustics,  729 

Anodynes  and  anaesthetics,  729 
Drugs   dilating    the  pupil  and  relaxing 
the  accommodation — mydriatics. 

Atropine  and  Homatropine,  276 

Cocaine,  298 

(Gelseminine,  263) 

Drugs   contracting   the    pupil    and    the 
ciliary  muscle — myotics. 

Physostigmine  or  Eserine,  320 

Pilocarpine,  311 

(Muscarine,  311) 


INDEX. 


The  preparations  are  not  mentioned  in  the  index  unless  when  they  are  met  with  in  the 
text  apart  from  the  chief  constituent — e.  g,,  Tinctura  digitalis  will  be  found  under  Digitalis ; 
but  Lead  plaster  is  indexed,  because  it  occurs  apart  from  lead.  For  metallic  salts,  see  the 
text  under  the  metal — e.  g.,  for  Mercury  perchloride,  see  Mercury. 


A  BIES  excelsa,  86 
A     Abrin,  84,  721 
Abrus  precatorius,  721 
Absinthe,  426 
Absorption  from  the  alimentary  tract,  32 

lungs,  32 

rectum,  34 

skin,  33,  49 

subcutaneous  tissues,  33 

wounds,  34 
Acacia,  47 

catechu,  113 
A.  C.  E.  mixture,  179 
Aceta,  40 
Acetal,  127 
Acetaldehyde,  425 
Acetanilide,  369,  380 
Acetate  of  ammonium,  550 
Acetates,  549 
Acetic  acid,  563 

ether,  71,  180 
Acetone-chloroform,  127 
Acetoperacid,  588 
Acetophenone,  127 
Acetphenetidine,  380 
Acetylene,  126 
Acid,  acetic,  563 

agaric,  297 

angelic,  334 

arabinic,  47 

arsenic,  604 

arsenious,  604,  616 

benzoic,  387,  419 

boracic,  578 

boric,  578 

bromacetic,  127 

butyric,  127 

cacodylic,  604 

caffeotannic,  353  (note) 

cambogic,  103 

camphoric,  298,  426,  431,  433 

carbolic,  385,  393,  397 

carbonic,  580 

cathartinic,  99 

cetraric,  59 

chavacinic,  72 

chloracetic,  127 

chromic,  591,699 

chrysophanic,  99,  102 


Acid,  cinnamic,  386,  419,  420 
citric,  569 
cresotinic,  386,  417 
crotonoleic,  98 
digallic,  112 
ergotinic,  472,  478 
filicic,  116 
flavaspidic,  116 
formic,  563 
gallic,  109,  112 
gallotannic,  112 
gymnemic  302  (note) 
hydriodic,  510 
hydrobromic,  504 
hydrochloric,  561 
hydrocyanic,  68,  238 
hydrofluoric,  521,  562 
hydrosulphuric,  575 
jalapinic,  103 
lactic,  564 
lupulinic,  58 
meconic,  206 
muriatic,  561 
nitric,  560 

nitrohydrochloric,  561 
ophelic,  59 
opianic,  229 
osmic,  702 
oxalic,  564 
oxybenzoic,  417 
oxynaphtoic,  417 
pannic,  116  (note) 
phosphoric,  562  • 
picramic,  421 
picric,  421 
piperinic,  72 
polygalic,  347 
propionic,  125 
prussic,  48,  68,  238 
pyrogallic,  385,  402 
quillaiac,  347 
quinic,  353,  549 
quinonic,  353  (note) 
ricinoleic,  98 
salicylic,  385,  386,  408 
santonin  ic,  120 
selenic,  702 
selenious,  702 
sclerotinic,  478 


733 


734 


INDEX. 


Acid,  sozoiodolic,  519 

sozolic,  417 

sphacelinic,  472 

sulfanilic,  512 

sulphuric,  560 

sulphurous,  562  f 

tannic,  109 

tartaric,  564 

telluric,  702 

trichloracetic,  563 

tropic,  276 

valerian  ic,  73 
Acids,  37,  555 

fatty,  563 

of  the  methane  series,  127,  563 

organic,  563 
Acocanthera,  435 
Acoines,  311 
Aconine,  328,  332 
Aconite,  comparison  with  antipyretics,  383 

digitalis,  455 
Aconitine,  328 
Aconitum,  328,  333 
Acorin,  70 
Action,  cumulative,  28 

relation  between  chemical  composition 
and  pharmacological,  24 

remote,  local,  indirect,  general,  23 
Actol,  591 
Adeps,  50 

lanae,  50 

Adhesive  plaster,  88,  728 
Adipis,  oleum,  51 
Adjuvants,  28 
Administration  of  drugs,  30 
Adonidin,  436 
Adonis,  435 
Adrenal  extract,  459 
Adrenalin,  459,  462 
^Ether,  177 

aceticus,  180 

^Etheris  nitrosi  spiritus,  470 
^Ethylis  carbamas,  193 

chloridum,  177 
Affinity,  elective,  of  drugs,  22 
Agaric,  297 
Agaricin,  297 
Agaricus,  297 

muscarius,  311 
Age  in  relation  to  dose,  25 
Agropyrum  repens,  48 
Agrostemma,  347 
Ague,  brass-founders',  684 
Agurine,  251 
Airol,  695 

Alanin-mercury,  654 
Alapurin,  50 
Albaspidin,  116 
Alcohol,  86,  127,  129 

amyl,  144 

butyl,  126,  144 

food  value  of,  139 

methyl,  144 

propyl,  125,  126,  144 
Alcohol-chloroform  group,  125 
Alcoholic  preparations,  39 


Alcoholism,  chronic,  150 
Aldehyde,  128 

formic,  423 

Alkaline  earths.      See    Calcium,  Barium, 
Strontium. 

carbonates,  540 
'hydrates,  540 
Alkaloids,  35 
Alkasal,  697 
Allspice,  67 
Almond,  238 
,    bitter,  67,  238 

oil,  51 

sweet,  48 
Aloe,  101 
Aloes,  99 
Aloin,  57,  99 
Alsol,  697 
Althaea,  47 
Alum,  624,  695 

ammonioferric,  664 
Alumen,  697 
Aluminium,  695 
Alumnol,  697 
Amanita,  311 
Amidocamphor,  426 
Ammonia,  551 
Arnmoniacum,  87 
Ammonias,  substituted,  499 
Ammoniated  mercury,  650 
Ammonium  acetate,  550 

bases,  499 

benzoate,  419 

bromide,  504 

carbonate,  551 

chlorate,  522 

chloride,  499 

citrate,  553 

iodide,  510 

salts,  258,  499 
Amygdala  amara,  67,  238 

dulcis,  48 

Amygdalae,  oleum  expressum,  51 
Amygdalin,  48,  67,  238 
Amyl  alcohol,  144 

nitrite,  464,  465 
Amylamine,  722 
Amylene,  126 

hydrate,  126,  191,  193 
Amylquinine,  258 
Amylum,  48 
Anacardium,  92 
Anacyclus,  72 
Anaesthesia,  general,  153 

infiltration,  307 

intraspinal,  308 

local,  180,  307 

regional,  308 

subarachnoid,  308 
Anaesthesin,  310 
Anaesthetics,  general,  153 

local  action  of,  180 

mixtures  of,  179 

preparations  of,  177,  180 
Anagallis,  707 
Analgen,  369 


INDEX. 


735 


Anamirta,  431 
Andira  araroba,  102 
Anemone,  92 
Aneson,  127 
Anesthol,  179 
Anethi  fructus,  67 
Angostura  bark,  59 
Anhalonium,  228 
Aniline,  35,  369,  424 
Animal  extracts,  710 

soap,  727 
Anion,  484 
Anise,  67 

oil  of,  68 
Anisol,  386,  400 
Anodyne,  Hoffman's,  180 
Antacids,  545 
Antagonistic  effects,  29 
Anthelmintics,  115 
Anthemis,  67 
Anthracene  purgatives,  99 
Anthraquinone,  99 
Anthrarobin,  103 
Antiarin,  436 
Antiaris,  435 

Antidote,  the  arsenic,  666 
Antifebrine,  369,  380 
Antihydrotics,  298 
Antimoniuretted  hydrogen,  633 
Antimony,  48,  621/629 
Antinosin,  519 
Antipyretics,  369 
Antipyrine,  369,  380 
Antiricin,  721 
Antiseptic  solution,  597 
Antiseptics,  385 
Antithermine,  369 
Antivenin,  721 
Antozone,  587 
Apalache  tea,  244 
Aperients,  94 
Apocodeine,  107,  236 
Apocynin,  436 
Apocynum,  435 
Apolysine,  370 
Apomorphine,  234 
Apple  seeds,  238 
Aqua  regia,  561 

tofana,  603 
Aquse,  38 

hydrogen  i  dioxide,  589 

of  volatile  oils,  70 

rosae,  unguentum,  50 
Aqueous  preparations,  38 
Arabin,  47 
Araroba,  103 
Arbutin,  77 

Arctostaphylos  uva  ursi,  77 
Argentamine,  691 
Argenti  cyanidum,  243 
Argentic  preparations,  690 
Argonin,  691 
Argyria,  688 
Aricine,  353  (note) 
Aristochine,  364 
Aristol,  519 


Aristolochia,  57,  59 
Aristolochine,  57 
Armoracia,  72,  88 
Armoracise,  spir.  co.,  69 
Arnica,  67,  86 
Arnicin,  69 
Aromatic  bitters,  70 

elixir,  69 

fluidextract,  powder,  71 

series,  385 

spirit,  70 

Arsenate,  iron,  667 
Arseni  iodidum,  617 

trioxidum,  616 
Arsenic,  603 

antidote,  667 

Arseniuretted  hydrogen,  616 
Arsenous  acid,  604,  616 
Arsine,  616 
Artemisia,  120 
Asafcetida,  73 
Asagrsea,  334 
Aseptol,  417 
Asiatic  pill,  616 
Aspidin,  116 
Aspidinol,  116 
Aspidium,  116 
Aspidosamine,  352 
Aspidosperma,  352 
Aspirin,  386,  414 
Asseline,  722 
Astragalus,  77 
Astringents,  metallic,  624 

vegetable,  109 
Atropa,  277,  291 
Atropamine,  277 
Atropine,  234,  276,  292 
Atroscine,  277 
Attar  of  roses,  68 
Aurantii  cortex,  67 

vinum,  145 
Auri  chloridum,  698 
Azulene,  61 

B^EL  fruit,  59 
Balsam,  37,  419 
Canada,  86 
copaiba,  76 
gurjun,  77 
of  Peru,  419 
traumatic,  419 
of  Tolu,  419 

Balsamodendron,  88 

Barbadoes  nuts,  97  (note) 

Barbaloin,  99 

Barium,  435,  572 

Barley,  48 

Barosma,  77 

Basham's  mixture,  667 

Baths,  490 

iron  and  steel,  662 

Bearberry,  77 

Bebeerine,  59 

Bebeeru  bark,  59 

Bebirine,  59 

Beers,  145 


736 


INDEX. 


Belladonna,  276,  291 

plaster,  728 
Belladonnine,  277 
Bellatropine,  277 
Bengal  quince,  59 
Benne,  oil  of,  51 
Benzaconine,  328,  332 
Benzanilide,  369 
Benzene,  385,  392 
Benzoates,  418 
Benzoic  acid,  386,  418 
Benzoin,  419 

flowers  of,  419 
Benzoinated  lard,  50 
Benzol,  385,  392 
Benzoperacid,  588 
Benzoylecgonine,  298,  306 
Benzoylmorphine,  216 
Benzoylperoxide,  588 
Berberine,  55,  57,  58,  229 
Bergamot,  oil  of,  68 
Beryllium,  495  (note),  696 
Beta-eucaine,  310 
Betol,  386,  412 
Betula?,  ol.  vol.,  68,  413 
Bhang,  232 
Biberine,  59 
Bicarbonates,  540,  545 
Bichromate,  699 
Bile,  96,  708 
Birch,  oil  of,  83,  86,  412 
Bismuth,  624,  688 
Bitter  almonds,  oil  of,  68,  238 
Bitters,  37,  55 

aromatic,  70 
Bittersweet,  347,  351 
Black  draught,  101 

drop,  219,  220 

wash,  653 
Blackberry,  113 
Blaud's  pills,  666 
Blazing  star,  347 
Bleaching  powder,  583 
Blister,  flying,  90,  628 
Blistering  collodion,  91 
Blood,  therapeutic  use  of,  669 
Bloodroot,  227 
Blue  mass  ointment,  652 

pill,  652 
Blumea,  426 
Boletus  laricis,  297 
Bone  black,  578 

marrow,  extract  of,  718 
Bones,  burned,  572 
Boracic  acid,  578 
Bond,  697 
Borax,  578 
Boric  acid,  578 
Borneo-camphor,  74,  426 
Borneol,  426,  430 
Bornylamine,  426 
Boroglycerin,  579 
Bougies,  31 
Brandy,  72,  145 
Brassfounders'  ague,  684 
Brassica,  89 


Brayera,  118 

Bromacetic  acid,  127 

Bromal,  191 

Bromated  camphor,  426,  503 

Bromates,  525 

Bromelin,  707 

Bromides,  500 

Bromine,  582 

Bromism,  500 

Bromoform,  128,  191,  193 

Bromol,  397 

Bromum,  583 

Broom,  tops  of,  264 

Brown  mixture,  48,  219 

Brown-Sequard's  fluid,  718 

Brucine,  195,  203 

Bryony,  103 

Buchheim's  classification,  42 

Buchu,  77 

Buckthorn,  102 

Bufonin,  435  (note) 

Bufotulin,  435  (note) 

Bunge's  theory  of  iron,  658 

Burgundy  pitch,  86 

plaster,  728 
Burnett's  solution,  686 
Buttonbush,  422  (note) 
Butyl  alcohol,  144 

chloral,  127, 190,  193 
Butylamine,  722 
Butyrates,  550 
Butyric  acid,  127 
Buxine,  55,  58 

CACAO,  244,  258 
butter,  31,  40,  254,  727 
Cachets,  41 

Cacodylates,  618  (note) 
Cacodylic  acid,  604 
Cactacese,  228 

Cactus  grandiflorus,  435  (note) 
Cade,  oil  of,  405 
Cadmium,  701 
Caesium,  495 
Caffeine,  244 
Cajuput,  oil  of,  68 
Calabar  bean,  195,  320,  324 
Calabarine,  195,  203,  320 
Calamus,  70 
Calcis,  liquor,  570 
Calcium,  565 

bromide,  504,  572 

carbonate,  571 

chloride,  570 

glycerophosphate,  572 

hydrate,  570 

hypochlorite,  583 

hypophosphite,  530 

lactophosphate,  572 

peroxide,  589,  590 

phosphate,  572 

sulphate,  572,  728 

sulphide,  575 

Calefaciens,  emplastrum,  728 
Cali  nut,  320 
Calomel,  651 


INDEX. 


737 


Calumba,  58 
Calumbin,  56,  57 
Calx,  570 

chlorata,  583 

sulphurata,  575 
Cambogia,  105 
Camphor,  426 

com.  tincture,  220 

monobromated,  426,  503 
Camphoric  acid,  426,  431 
Camphorol,  426 
Canada  balsam,  86 
Canadian  hemp,  435 

moonseed,  59 
Canadine,  55,  229 
Cane  sugar,  54 
Cannabin,  232 
Cannabinol,  232 
Cannabis  Indica,  2S2 
Canquoin's  paste,  686 
Cantharidin,  89 
Cantharis,  89 
Caoutchouc,  728 
Capsicum,  72,  93 
Capsule,  suprarenal,  459 
Capsules,  31,  41 
Caraway,  67 
Carbo,  578 

Carbolic  acid,  385,  393,  397 
Carbon,  578 

tetrachloride,  179 
Carbonates,  540 
Carbonic  acid,  580 
Carbylamine,  239 
Cardamom,  67 
Cardol,  92 
Carica,  707 
Carlsbad  salts,  537 
Carminatives,  62,  72,  74 
Carniferrin,  668 
Carolina  jasmine,  263 
Carragheen,  48 
Carron  oil,  570 
Carum,  67 
Caryophyllum,  67 
Caryophyllus,  67 
Casca  bark,  435 
Cascara  sagrada,  102 
Cascarilla,  70 
Cassia  acutifolia,  101 

angustifolia,  101 

fistula,  54 

purging,  54 
Cassise  pulpa,  54 
Castile  soap,  727 
Castor  oil,  97,  720 
Catalase,  588 

Cataplasma,  41.     See  Poultices. 
Catechu,  112 
Cathartics,  94 

saline,  530 
Cathartin,  99 
Cations,  484 
Caustic,  lunar,  690 

mitigated,  690 

potash,  545 

47 


Caustic  soda,  545 

toughened,  690 
Cayenne  pepper,  72 
Cephseline,  339 
Cephalis,  339 
Cephalanthin,  422  (note) 
Cera,  51,  727 
Cerates,  30,  40,  727 
Ceratum,  51 

camphorse,  87 
Cerberin,  437 
Cerium,  695 
Cetaceum,  51 
Cetraria,  48 
Cetraric  acid,  48,  59 
Cetrarin,  57 
Cevadilla,  334 
Cevadilline,  334 
Cevadine,  334 
Cevine,  334 
Chalk,  571 

Chalybeate  preparations,  664 
Chamselirium,  347 
Chamomile,  67 
Champagne,  146,  580 
Charas,  232 
Charcoal,  577 
Charta,  41 
j  Chaulmoogra,  93 


!  Chavicine,  72 

j  Chavicinic  acid,  72 


i  Cheiranthin,  437 

Cheiranthus,  437 
i  Chelerythrin,  227 
i  Chelidonine,  227 
i  Chelidonium,  227 

Chemical  composition  and  action,  24 

Chenopodium,  124 

Cherry,  Virginian,  68,  238 
water,  72 

Children,  dose  for,  25 

Chili  saltpeter,  528 

Chillies,  73 

Chimaphila,  77 

Chinaphenine,  364 

Chinotropine,  549 

Chirata,  58 

Chiretta,  58 

Chloracetic  acid,  127 

Chloral,  127,  186,  192 

Chloralamide,  127,  190,  193' 

Chloralformamide,  190,  193 

Chloralose,  127,  191 

Chlorates,  522 

Chloretone,  127,  191,  193 

Chlori,  liquor,  583 

Chlorides,  486 

Chlorinated  lime,  583 
soda,  583 

Chlorine,  582 

Chlorodyne,  180 

Chloroform,  86,  127,  153,  177 

Chlorphenol,  386,  397 

Chlorum,  583 

Chocolate,  244,  258 

Cholagogues,  94, 


738 


INDEX. 


Chondrodendron,  59 
Chondrus,  48 
Christmas  rose,  435 
Chromic  acid,  591,  699 
Chromium,  699 
Chromotherapeutics,  423 
Chrysarobin,  102 
Chrysophanic  acid,  99,  102 
Chrysotoxin,  473 
ChuiTus,  232 
Cicuta,  432 
Cicutoxin,  432 
Cinchona,  353 

red,  353  (note) 
Cinchonamine,  353  (note) 
Cinchonidine,  353 
Cinchonine,  353 
Cineol,  120 
Cinnaldehyde,  71 
Cinnamic  acid,  386,  419,  420 

aldehyde,  71 

Cinnamomum  camphora,  426 
Cinnamon,  67 
Cinnamyl-cocaine,  298 
Citrates,  550 
Citric  acid,  564 
Citrine  ointment,  654 
Citrophen,  370 
Citrullus  colocynthis,  104 
Clarets,  145 

Classification  of  drugs,  41 
Claviceps  purpurea,  472 
Cloves,  67 
Clysma,  41 
Clyster,  41 
Coal-tar,  405 
Cobalt,  701 
Coca,  298,  306 
Cocaine,  298,  306 
Cocainization,  intraspinal,  308 

subarachnoid,  308 
Cocamine,  298,  305 
Coccus,  55 
Cochineal,  55 
Cochlearia,  73,  88 
Cocoa,  244,  258 
Codamine,  206 
Codeine,  206,  216,  220 
Cod-liver  oil,  722 
Coffee,  244,  252 
Coffeon,  252 
Cola,  244 
Colchicum,  343 
Cold,  85 

bath,  382 

cream,  50,  69 

pack,  318 
Coleoptera,  89 
Colic,  painter's,  673 
Colica  pictonum,  673 

saturnina,  673 
Collodia,  30,  40,  728 
Collodium,  30,  40,  728 

cantharidum,  728 

flexible,  728 

stypticum,  112,  728 


Collodium  vesicans,  91,  728 

Colloid  substances,  45 

as  demulcents,  45 
as  purgatives,  54 
relations  of,  to  salts,  483 

Colloxylin,  728 

Colocynth,  103 

Cologne,  eau  de,  68 

Colophony,  87 

Columbo,  55 

Commiphora,  88 

Common  salt,  486 

Compresses,  hot-water,  85 

Concusconine,  353  (note) 

Condurango,  57,  59 

Condy's  fluid,  591 

Confectiones,  40 

Conhydrine,  259 

Coniine,  259,  326 

Conium,  259 

Conjunctiva,  applications  to,  31 

Conquairamidine,  353  (note) 

Conquairamine,  353  (note) 

Conquinamine,  353  (note) 

Conquinine,  353,  362 

Convallamarin,  435 

Convallaria,  435 

Convolvulin,  103 

Convolvulus,  105 

Copaiba,  74  • 

Copaiva,  74 

Copper,  624,  680 
arsenite,  604 

Coral,  572 

Coralline,  572 

Coriarnyrtin,  432 

Coriander,  67 

Coriaria,  432 

Corncockle,  347 

Cornsilk,  77 

Cornsmut,  480 

Comutine,  472 

Coronilla,  435 

Coronillin,  436 

Corrosive  sublimate,  650 

Cotarnine,  229 

Goto  bark,  58,  59 

Cotoin,  58,  59 

Cottonroot  bark,  480 

Cottonseed  oil,  51 

Couchgrass,  48 

Counter-irritation,  78 

Court  plaster,  728 

Cranesbill,  113 

Crede's  colloid  silver,  691 

Creolin,  400 

Creosols,  386,  407 

Creosote,  387,  406 

Cresalol,  386,  412 

Cresol,  386,  399 

Cresotinic  acid,  386,  417 

Creta,  571 

pulv.  cum.  opio,  220 

Crocus,  55 

Crotin,  721 

Croton-chloral,  127,  190 


INDEX. 


739 


Croton  oil,  97 
Crotonoleic  acid,  97 
Croton  tiglium,  79,  99,  721 
Cruciferse,  oils  of,  61,  72,  88 
Ciyptopine,  206,  218 
Cubebin,  74 
Cubebs,  74 

Cucumber,  squirting,  103 
Cucurbita,  120 
Culver's  root,  105 
Cumulative  effects,  28 
Cupratin,  683 
Cuprea,  353 
Cupric  sulphate,  682 
Cuprohaemol,  682 
Cura£oa,  72 
Curara,  254,  320 
Curarine,  254 
Curd  soap,  727 
Curine,  254 
Currier's  sumach,  432 
Cuscamidine,  353  (note) 
Cuscamine,  353  ( note ) 
Cusconidine,  353  (note) 
Cusconine,  353  (note) 
Cusparia,  59 
Cusso,  118 
Cutol,  697 
Cuttlefish,  572 
Cyanides,  238 
Cyanogen,  238 
Cyclamen,  347 
Cynoctonine,  332 
Cypripedium,  67 
Cytisus  scoparius,  264 

PkANDELION,  58 
\J     Daphne  mezereum,  95 
Datura,  277,  291 
Daturine,  277 
Dead  tongue,  432 
Deadly  nightshade,  277 
Decocta,  39 
Decoctions,  39 

Degeneration,  fatty,  591,  593 
Delirium  tremens,  150 
Delphinium,  328 
Demulcents,  45 
Depression,  depressants,  20 
Derivation,  theory  of,  78 
Dermatol,  694 
Dermol,  695 
Dextrins,  45 
Diacetylperoxide,  588 
Diachylon  ointment,  50 

plaster,  677,  728 
Diastase,  707 
Didymium,  495  (note) 
Diethylendiamine,  549 
Diffusion,  481 
Digallic  acid,  112 
Digestive  ferments,  705 
Digitalein,  436 
Digitalin,  436 
Digitalines,  451 
Digitaliresin,  432 


Digitalis,  435 

comparison  with  aconite,  333 

with  antipyretics,  383 
Digitonin,  47,  436 
Digitophyllin,  436 
Digitoxin,  436 
Dihydrolutidine,  722 
Dill,  67 
Dionea,  707 
Dionine,  216 
Diosphenol,  77 
Dioxide  of  hydrogen,  587 
Dipterocarpus-alatus,  76 
Discs,  40 

Disease,  effect  of,  on  dose,  29 
Disinfectants,  385 
Dissociation  of  salts,  484 
Diterpenes,  61 
Diuretin,  251 
Dogwood,  422  (note) 
Donovan's  solution,  617,  651 
Dorema  ammoniacum,  87 
Dormiol,  191 

Dose,  conditions  modifying  the,  25 
Dover's  powder,  219,  220,  342 
Drastics,  94 
Dropwort,  water,  432 
Drosera,  707 
Drugs,  17 

action  of,  20 

chemical  character  of,  34 

classification  of,  41 

conditions  modifying  the  effect  of,  25 

definition  of,  17 

elective  affinity  of,  22 
Dryobalanops,  426 
Dryopteris  filix-mas,  117 
Duboisia  Hopwoodii,  266 

myoporoides,  277 
Duboisine,  277 
Dulcamara,  347 
Dulcamarine,  347 
Dulcin,  55 
Dusting-powders,  53 
Dyes,  aniline,  423 

EASTON'S  syrup,  363 
Eau  de  cologne,  69,  145 
Ecballium,  105 
Eccoprotic,  94 
Ecgonine,  276,  298,  306^ 
Effects  of  drugs,  conditions  affecting,  25 
Effervescing  purgatives,  537 
Eigon,  516 
Elastica,  728 
Elaterin,  103 
Elaterium,  103,  105 
Elderflower,  67 
Elective  affinity  of  drugs,  22 
Electuaries,  40 
Elemi,  88 
Elixirs,  39 

aromatic,  68 
Elm,  slippery,  47 
Eloeoptene,  61 
Embrocations,  40 


740 


INDEX. 


Emetics,  237 

Emetine,  339 

Emodin,  99 

Emollients,  49 

Emplastra,  30,  41,  727 

Emplastrum  calefaciens,  91,  728 

Emulsa,  39 

Emulsin,  48,  67,  238 

Emulsions,  32,  39 

Endermic,  33 

Enema,  31,  41 

Epinephrine,  435,  449 

Epsom  salts,  536 

Erbium,  495  (note) 

Ergochrysin,  473 

Ergot,  472 

Ergotin,  477 

Ericolin,  77 

Erigeron,  oil  of,  68 

Errhines,  31 

Erythrol  tetranitrate,  464,  469 

Erythrophoeine,  436 

Erytbropbloeum,  435 

Erytbroxylon,  306 

Eseridine,  320 

Eserine,  320 

Essences,  71 

of  volatile  oils,  69 
Essential  oils,  61 
Esters,  127 
Etber,  71,  126,  153,  177 

acetic,  71,  180 

nitric,  464 

nitrous,  464 
Ethereal  oils,  61,  86,  387 

salts,  127 
Etbyl  alcohol,  126 

bromide,  128,  178 

carbamate,  193 

chloride,  177,  179,  181     . 

ether,  127 

nitrite,  65,  470 

oxide,  177 
Ethylene  bromide,  178 

chloride,  127,  177 
Ethylidene  chloride,  127,  177 
Ethylmorphine,  216 
Eucaine,  310 
Eucalypti  gummi,  113 
Eucalyptol,  70,  401 
Eucalyptus,  66,  67 

oil  of,  68,  401 
Eudoxine,  519,  695 
Eugenol,  71 
Eumydrine,  291 
Euonymin,  103,  437 
Euonymus,  103,  105,  437 
Euphorbin,  93 
Euphorin,  370 
Euquinine,  364 
Europhen,  519 
Eurotium  oryzse,  708 
Exalgine,  369,  380 
Exodin,  102 

Expectorants,  nauseating,  237 
Extracts,  40 


Extracts,  animal,  710 

fluid,  liquid,  39 
Extractum  aromaticum  fluidum,  71 

FABTANA,  77 
Fats,  49 
Fatigue,  255 

Fatty  degeneration,  591,  593 
Fel  bovis,  710 
Fennel,  67 

Ferments,  digestive,  705 
Ferratin,  668 
Ferric  preparations,  664 

salts.     See  Iron. 
Ferrocyanides,  239,  530,  539 
Ferrous  preparations,  664 
Ferruginous  preparations,  665 
Ferula,  73 

galbanum,  87 
Ficus,  54 
Figs,_54,  707 
Filicic  acid,  116 
Filix  mas,  116 
Flavaspidic  acid,  116 
Flavoring  substances,  54 
Flexible  collodion,  728 
Flowers  of  sulphur,  576 
Fluorides,  521 
Flying  blister,  92 
Foeniculum,  67 
Formaldehyde,  423 
Formaline,  423 
Formates,  550 
Formic  acid,  563 
Fowler's  solution,  617 
Foxglove,  435 
Frangula,  99,  102 
Frangulin,  99 
Frankincense,  85 
Friar's  balsam,  419 
Fruit  juices,  559 
Frumenti,  spiritus,  145 
Fuller's  earth,  53 
Fumigation,  mercurial,  648 
Fusel  oil,  144 

GADUS,  722 
Galbanum,  73,  87 
Galipine,  59 
Galla,  113 

Gallacetophenone,  403 
Gallal,  697 
Gallic  acid,  109, 112 
Gambir,  112 
Gamboge,  103 
Ganja,  232 
Garcinia,  105 
Gargarisma,  31 
Gargle,  31  ^ 
Gas,  laughing,  182 
Gaultherise,  oleum,  68,  413 
Gelatin,  569 

capsule,  41 
Gelsemine,  195,  202,  263 
Gelsemium,  259,  263 
General  action,  23,  31 


INDEX. 


741 


General  anaesthetics,  153 

Genitourinary  disinfectants,  oils  used   as, 

75 

Gentian,  58 
Geranium,  113 
Gigartina,  48 
Gila  monster,  721 
Gin,  72,  145 
Ginger,  68,  72 
Gland  extracts,  711 
Glandulae  suprarenales,  462 
Glauber's  salt,  536 
Glucose,  54 
Glucosi,  syrupus,  54 
Glucosides,  36 
Glusidum,  55 
Glycerin,  40,  51 

trinitrate,  464,  469 
Glycerites,  40 
Glyceritum  amyl,  51 

vitelli,  51 

Glycerophosphates,  539 
Glycerylis  nitras,  470 
Glycol,  126 
Gly  cos  ides,  36 
Glycyrrhiza,  48 
Glycyrrhizin,  48 
Gnoscopine,  206 
Goa  powder,  102 
Gold,  698 
Golden  seal,  229 
Gonolobus,  59 
Gorite,  589 
Gossypii,  radicis  cortex,  480 

seminis,  ol.,  51 

Goulard's  extract,  cerate,  lotion,  677 
Granatum,  19 
Grape  cure,  59 
Gray  oil,  653 

powder,  652 
Greens,     Scheele's,    Schweinfurt's,    Paris, 

604 

Gregory's  powder,  100 
Grey  oil,  653 

powder,  652 
Griffith's  mixture,  666 
Guaiacol,  386,  407 

carbonate,  386,  407 

salol,  412 
Guaiacum,  87 
Guarana,  244,  251 
Gum,  37,  45 

arabic,  47 
Gum-resins,  37 
Gun-cotton,  728 
Gurjun  balsam,  76 
Gymnema  silvestre,  302  (note) 
Gymnemic  acid,  302  (note) 
Gynocardia,  93 
Gypsophila,  347 
Gypsum,  572,  728 

TT7EMATOGEN,  668 
11     Haematoxylon,  113 
Hsemogallol,  669 
Hemoglobin,  669 


Hjemol,  669 
Hagenia,  18 
Hamamelis,  113 
Hard  soap,  727 
Hamack's  experiment,  323 
Hartshorn,  spirit  of,  552 
Hashish,  232 
Heat,  86 

Heavy  metals,  621 
Hedeoma,  67 
Hedonal,  127,  191,  193 
Hellebore,  green,  white,  334 
Helleborein,  436 
Helleborus  niger,  435 
Heloderma,  721 
Hemidesmus,  351 
Hemlock,  259 

water,  432 
Hemp,  Canadian,  435,  452 

Indian,  232 
Henbane,  277 
Hepar  sulphuris,  575 
Hesperidin,  69 
Heteroxanthine,  244 
Henamethylenamine,  425 
Hexylamine,  722 
Hock,  145 

Hoffmann's  anodyne,  180 
Holocaine,  311 
Homatropine,  277,  290 
Homococamine,  298 
Homochelidonine,  227 
Homocinchonidine,  353  (note) 
Homoisococamme,  299 
Honey,  39,  54 
Hops,  58 
Hordeum,  48 
Horehound,  67 
Horseradish,  69,  72 
Hot  compresses,  86 
Humulus,  59 
Hunyadi-janos,  537 
Hydragogues,  94 
Hydrargyrum,  640 
Hydrastine,  229,  230 
Hydrastinine,  229,  230 
Hydrastis,  229 
Hydrates,  540 
Hydriodic  acid,  510 
Hydrobromic  acid,  504 
Hydrochloric  acid,  561 
Hydrocinchonine,  353  (note) 
Hydrocotarnine,  206,  217 
Hydrocyanic  acid,  238 
Hydrofluoric  acid,  521,562 
Hydrogen,  antimoniuretted,  633 

arseniuretted,  616 

dioxide,  587 

ion,  555 

peroxide,  587 

phosphuretted,  592 

sulphuretted,  575 
Hydroquinidine,  353  (note) 
Hydroquinine,  353  (note) 
Hydroquinone,  77,  385 
Hydrosulphuric  acid,  575 


742 


INDEX. 


Hygrine,  299  (note) 
Hyoscine,  276,  289,  292 
Hyoscyamine,  276,  288,  292 
Hyoscyamus,  277,  291 
Hypertonic  solutions,  482 
Hypnal,  192,  369 
Hypnone,  127,  192 
Hypnotics,  186 
Hypochlorites,  583 
Hypodermic  injection,  33 
Hypophosphites,  530 
Hypophysis,  extract  of,  718 
Hypoquebrachine,  352 
Hyposulphites,  529 
Hypotonic  solution,  482 

ICELAND  moss,  48,  59 
1     Icythyocolla,  728 
Ichthyol,  387,  407 
Idiosyncrasies,  27 
Ignatia,  195 
Ilex,  Paraguay,  244 
Immunity,  28,  720 
India-rubber,  728 
Indian  corn,  78 

hemp,  232 

tobacco,  275 
Indirect  action,  23 
Infiltration  anaesthesia,  307 

fatty,  592 

Infundibular  body,  718 
Infusa,  39  \ 

Infusions,  39 
Ingluvin,  707 
Injection,  hypodermic,  33 

intravenous,  34 

subcutaneous,  33 
Insect  poisons,  721 
Internal  secretions,  710 
Intestine,  absorption  from,  32 
Intraspinal  cocainization,  308 
Intravenous  injection,  34 
Inunction,  33,  646, 653 
lodalbumin,  716 
lodates,  525 
Iodides,  506 
Iodine,  513 
lodipin,  516 
lodism,  506,  514 
lodoform,  517 
lodol,  519 
lodolen,  516 
lodolum,  520 
lodospongin,  716 
lodothyrin,  711 
lodum,  515 
Ions,  484 
Ipecacuanha,  339 
Ipecacuanha  pulvis  co.,  220 

cum  scilla,  pil.,  220 
Ipomo3a,  105 
Irish  moss,  48 
Iron,  624,  655 

arsenate,  617 

hypophosphite,  530 
Irritants,  20 


Irritants,  skin,  78 
Irritation,  20 
Isinglass,  728 

Isoamyl  alcohol,  tertiary,  126 
Isobutyl  nitrite,  468 
Isococamine,  298 
Isolichenin,  48 
Isonitriles,  239 
Isopelletierine,  119 
Isopilocarpine,  311 
Isopral,  192 
Isopunicine,  119 
Isoquinoline,  35,  262 
Isotonic  solutions,  482 
Itrol,  691 
Ivy  poison,  92 

TABOEANDI,  311,  317 
d      Jaborine,  311  (note) 
Jalapa,  105 
Jalapin,  103 
Jarnbul,  725 
James'  powder,  633^ 
Japaconitine,  328 
Jasmine,  yellow  or  Carolina,  263 
Jateorhiza,  58 
Jatropha,  97  (note) 
Javelje's  solution,  583 
Jecoris  aselli,  oleum,  724 
Jequirity,  721 
Jervine,  334,  339 
Jesuit's  drops,  419 
Juices,  40 
Juniper,  empyreumatic  oil  of,  405 

oil,  68 

sabina,  86 

tar  oil,  405 

KAIEINE,  369 
Kairoline,  369 
Kali  nut,  320 
Kamala,  120 
Kaolinum,  53,  727 
Ration,  484 
Kava-kava,  73 
Kelene,  179 
Keratin,  727 
Kermes  mineral,  633 
Ketones,  127 
Kino,  113 

pulvis  comp.,  220 
Kirschwasser,  72 
Kola,  244 
Kombe,  435 
Kosotoxin,  118 
Kousso,  118 
Krameria,  112 
Kresamine,  400 
Kryofine,  370 
Kummel,  72 

T  ABAEEAQUE'S  solution,  583 
L     Lactates,  550 
Lactation,  medication  during,  26 
Lactic  acid,  564 
Lactophenine,  370,  380 


INDEX. 


743 


Lactophosphate,  572 
Lactose,  54 
Lactuca,  234 
Lactucariurn,  234 
Lady's  slipper,  67 
Lamella-,  40 
Lanichol,  50 
Lanolin,  50 

Lanthanum,  495  (note) 
Lanthopine,  206 
Lappaconitine,  332 
Lard,  50 

oil  of,  51 
Largin,  691 

Larynx,  application  to,  31 
Laudanine,  206,  217 
Laudanosine,  206 
Laudanum,  219,  220 
Laughing  gas,  182 
Laurel,  67,  238 

camphor,  429 

leaves,  67,  238 

water,  69 

Laurocerasi  folia,  67,  70 
Laurocerasus,  238 
Lavender,  oil  of,  68 
Laxative,  94 
Lead,  624,  670 

iodide,  51 

palsy  and  arsenic,  607 

plaster,  728 
Lemon,  67 

essential  salts  of,  564 

juice,  564 

oil  of,  68 
Leptandra,  105 
Leptandrin,  103 
Lettuce,  234 
Levant  wormseed,  122 
Levico  water,  617 
Lichenin,  48 
Lily  of  the  valley,  435 
Lime,  564,  570 

chlorinated,  583 

hypophosphite,  530 

juice,  564 

phosphate,  carbonate,  53 

sulphurated,  575 
Limonis  cortex,  67 
Lini  oleum,  51 
Liniments,  40 
Linimentum  camphorae,  86 

chloroformi,  86,  180 

saponis,  86 
Linseed,  47 
.    oil,  51 
Linum,  47 
Lipanin,  723 
Liqueurs,  67,  71 
Liquidambar,  419 
Liquidextracts,  39 
Liquor  antisepticus,  579 

epispasticus,  91 

hydrogenii  dioxide,  589 
Liquores,  39 
Liquorice,  48 


Litharge,  677 
Lithium,  495 

benzoate,  419 

bicarbonate,  545 

bromide,  504 

carbonate,  545 

citrate,  536 

hydrate,  545 

salicylate,  413 
Liver  of  sulphur,  575 
Lizard,  poisonous,  721 
Lobelia,  275 
Lobeline,  266,  275 
Local  action,  23 

anaesthesia,  180,  307 
Logwood,  113 
Loretin,  519 
Losophan,  579 
Lotions,  39,  653 
Lozenges,  31,  40 
Lugol's  solution,  515 
Lunar  caustics,  690 
Lungs,  absorption  from,  32 

administration  by,  30 
Lupine,  264  (note) 
Lupinine,  264  (note) 
Lupulin,  58 
Lupulinic  acid,  57 
Lupulus,  58 
Lycaconitine,  333 
Lycetol,  549 
Lycopodium,  53 
Lysidine,  549 
Lysol,  400 
Lytta,  89 

MACE,  68 
Magisterium  bismuthi,  693 
Magnesia,  536 

fluid,  536 
Magnesium,  535 

carbonate,  536 

chloride,  530 

citrate,  530 

oxide,  530 

peroxide,  590 

salts,  535 

sulphate,  536 
Maize,  78 

fungus  of,  480 
Malakine,  370,  380,  412 
Malates,  530 
Male  fern,  116        _ 
Mallotus,  120 
Malonates,  554 
Malt,  54 

enzyme,  707 

extract,  707 
Maltine,  707 
Maltzyme,  707 
Mandragora,  277 
Mandragorine,  277 
Mandrake,  277 
Manganese,  700 
Mangani  dioxidum,  700 
Manicheel  tree,  93 


744 


INDEX. 


Maunitol  hcxanitrate,  464 
Marrubium,  07 
MarahmaJlow,  47 

Massa,  40 

Mastiehe,  102 

Mate,  244 

Materia  mediea,  definition  of,  19 

Matieo,  7(5 

Matriearia,  67 

Maydis  ustilago,  480 

Meals,  influence  of,  on  dose,  26 

Meeonie  acid,  206 

Meconidine,  206 

Medicated  waters,  38 

Medication.  local,  30 

Mel,  54 

Mellita,  39 

Menispermurn,  55 

eoceulus,  431 
Menstruation,  26 
Mentha,  67 
Menthane,  426 
Menthol,  71,  42M29,  728 
Mereurialisin,  637 
Meivury,  621-628,  634 

iodide,  510,  651 

sozoiodolate,  519,  654 
Mesotan,  416  (note) 
Metaeresol,  399 
Metadinitrobenzol,  421 
Metals,  heavy,  621 

minor,  698 
Metaphosphates,  535 
Methaeetine,  370 
Methyl  alcohol,  144 

bromide,  179 

chloride,  181 

coniine,  259 

hydroOjiiinone,  77 

morphine,  216 

salieylate,  68,  386,  412 

strychnine,  258 
Methyl-arbutin,  77 
Methylal,  127 
MethyJamine,  499 
Methylatropine,  291 
Methylene  bichloride,  178 

bine,  423 

Methylis  salicylas,  413 
Methylthionin,  423 
Meyer-Overton  theory  of  narcosis,  20,  127, 

166 

Mezeal  button,  228 
Mezcaline,  228 
Mezereum,  92,  93 
Milk  of  lime,  571 

sugar  of,  54 

of  sulphur,  576 
Mindererns,  spirit  of,  553 
Mineral  waters,  576,  582,  668 
alkaline,  547 
iron,  666 

Mint,  essence  of,  72 
Mist une,  39 
Mithridatism,  27 
Mitigated  caustic,  690 


Mixture,  39 

brown,  48 
Molasses,  54 
Molybdenum,  701 
Monkshood,  328,  333 
Monobromated  camphor,  426,  503 
Monoehlorphenol,  386,  397 
M ousel's  solution,  665 
Moonseed,  Canadian,  59 
Morphine,  206,  218 

comparison  with  antipyrine,  383 

poisoning,  atropine  in,  295 
Morphinism,  225 
Morpholine,  206 
Morrhwe,  oleum,  724 
Morrhuine,  722 
Morrhnol,  723 
Mosehus,  431 

Mouth,  administration  by,  30,  31 
Muawine,  437 
Mucilages,  39,  47 
Mucuna,  320 
Muriatic  acid,  561 
Muscale  buttons,  228 
Muscarine,  311,326 
Mushrooms,  311 
Musk,  74,  431 
Mustard,  72,  88 
Myoctonine,  333 
Myristica,  67 
Myronate,  88 
Myrosin,  88 
Myroxylon,  419 
Myrrha,  88,  102 

\TAPHTHALAN,  387 

ll     Naphthalene,  385,  402 

Naphtalol,  412 

Naphthylamine,  421 

Naphtol,  385,  403 

Narceine,  206,  217 

Narcosis,    Mayer-Overton    theory    of,   20, 

127,  166 

Narcotics  of  methane  series,  126,  186 
Narcotine,  206,  217,  229 
Nectandne  cortex,  59 
Neriin,  436 
Neriodorin,  436 
Nerinm,  435 
Neroli,  oil  of,  68 
Neurodine,  370,  380 
Neuronal,  193 
Newt,  432 
Ngai-camphor,  426 
Nickel,  701 
Nicotiana,  266,  273 
Nicotin,  266,  326 
Nightshade,  black,  347 

deadly,  277 
Nitrates,  464,  527 
Nitre,  528 

sweet  spirits  of,  469 
Nitric  acid,  560 

ethers,  464 
Nitriles,  239 
Nitrites,  464 


INDEX. 


745 


Xitrobenzol,  420 
Nitro-bodies,  464 
Nitroethane,  464 
Nitroglycerin,  464,  469 

and  digitalis,  456 
Nitrohydrochloric  acid,  561 
Nitromethane,  464 
Nitrous  ether,  464 

oxide,  182 

Nose,  application  to,  31 
Nosophen,  519 
Nut-gall,  113 
Nutmeg,  67 
Nuts,  Barbadoes,  97  (note) 

purging,  97  (note) 
Nux  vomica,  195 

OAK  BARK,  white,  113 
poison,  92 
Octane,  126 

(Enanthic  ethers,  72,  129,  145 
CEnanthotoxin,  432 
(Enanthylates,  550 
Oil.     See  Oleum. 

cod-liver,  722 

cotton-seed,  51 

fusel,  144 

of  roses,  67 
Oils,  49,  51 

essential,  61 

ethereal,  61 

purgative,  97 

volatile,  61 
Ointments,  30,  40,  50 
Olea,  51 
Oleander,  435 
Oleandresin,  432 
Oleandrin,  436 
Oleates,  40 
Oleites,  351 

Oleoresin  zingiberis,  68 
Oleoresins,  37 
Oleum  adipis,  51 

amygdalae  amarae,  67,  238 
expressum,  51 

anethi,  68 

anisi,  68 

aurantii  florum,  68 

bergamottae,  68 

betulae,  volatile,  68,  412 

cadinum,  405 

cajuputi,  68 

carui,  68 

caryophylli,  68 

chenopodii,  124 

cinereum,  653 

cinnamomi,  68 

copaibae,  76 

coriandri,  68 

crotonis,  97 

cubebae,  76 

erigerontis,  68 

eucalypti,  68 

foeniculi,  68 

gaultheriae,  68,  412 

gossypii  seminis,  51 


Oleum  hedeomae,  68 

jecoris  aselli,  724 

juniperi,  68,  86 

lavandulae  florum,  68 

limonis,  68 

lini,  51 

menthse  piperitae,  68 
viridis,  68 

morrhuae,  724 

myrciae,  68 

myristicae,  68 

olivae,  51 

phosphoratum,  601 

picis,  405 

pimentae,  68 

pini,  86 

ricini,  97 

rosae,  68 

rosrnarini,  68 

sabinae,  68,  86 

santali,  76 

sassafras,  68 

sinapis,  volatile,  89 

terebinthinfe,  86 

theobromatis,  727 

thymi,  68 

tiglii,  97 

Olive  oil,  46,  51,  723 
Oophorin,  719 
Ophelic  acid,  58 
Opianic  acid,  229 
Opium,  206 
Orange  flowers,  oil  of,  68 

peel,  67 

wine,  145 

Ordeal  bean,  320,  324 
Orexine,  59 
Organic  acids,  563 

iron,  655 

Organotherapeutics,  710 
Orphol,  695 
Orpiment,  603 
Orthocresol,  399 
Orthoform,  310 
Orthophosphates,  535 
Oscine,  276 
Osmic  acid,  702 
Osmosis,  482 
Osmotic  pressure,  482 
Otto  of  roses,  68 
Ouabaio,  435 
Ourouparia,  112 
Oxalates,  553 
Oxalic  acid,  564 
Oxgall,  710 
Oxybenzoic  acid,  417 
Oxygen,  585 
Oxymel,  39,  54 
Oxynaphtoic  acid,  386,  417 
Oxynarcotine,  206 
Ozone,  586 

PACK,  hot,  cold,  318 
Palmitates,  550 
Palsy,  painters',  673 
Panama  bark,  351 


746 


INDEX. 


Pancreas,  extract  of,  718 
Pancreatic  ferment,  706 
Pancreatin,  706 
Pannic  acid,  116  (note) 
Papain,  707 
Papaja,  707 
Papaveramine,  206 
Papaverine,  206,  217 
Papaveris  capsulae,  220 
Papaver  rhoeas,  55 

somniferum,  206 
Papayotin,  707 
Papers,  41 
Papoid,  707 
Paracotoine,  58 
Paracresol,  399 
Paraffin,  50 
Paraform,  424 
Paraguay  tea,  244 
Paraldehyde,  127,  189,  192 
Paralysis,  definition  of,  21 

and  fatigue,  relation  between,  255 
Paramidophenol,  370 
Paraxanthine,  244,  252 
Paregoric,  219,  429 
Pareira,  59 
Parilla,  yellow,  59 
Parillin,  347 
Paris  green,  604 

plaster  of,  572,  728 
Pathological   conditions    modifying    dose, 

Paullinia,  244 
Pawpaw,  707 
Payta,  352 
Paytanine,  352 
Pearson's  solution,  616 
Pelletierine,  119 
Pellitory,  72 
Pellote,  228 
Pennyroyal,  67 

oil,  67 

Pental,  126,  178 
Pentane,  126 
Pepo,  120 
Pepper,  72,  93 

black,  72 

Cayenne,  72 
Peppermint,  67 

oil  of,  68 
Pepsin,  705 
Pepsinum,  705 
Peracids,  588 
Perchlorates,  525 
Perchlorethane,  179 
Permanganates,  589 
Peronine  216 
Peroxide  of  hydrogen,  587 
Peroxides,  589 
Persodine,  589 
Persulphates,  589 
Peru,  balsam  of,  419 
Petrolate,  50 
Petroleum,  50 
Peyotl,  228 
Pharmacognosy,  19 


Pharmacological  action  and  chemical  struct- 
ure, 24 
Pharmacology,  definition  of,  and  relations 

to  biology  and  clinical  subjects,  17-19 
Pharmacopeia,  37 
Pharmacy,  19 
Pheasant's  eye,  435 
Phenacetine,  370,  380 
Phenanthren,  206 
Phenazone,  380 
Phenetidines,  370 
Phenetol,  386 
Phenocoll,  370,  380 
Phenol,  385,  393,  397 
Phenylhydrazine,  369 
Phenylis  salicylas,  414 
Phloretin,  725 
Phloridzin,  725 
Phosphates,  535 
Phosphidum  zinci,  601 
Phosphine,  601 
Phosphorated  oil,  601 
Phosphoric  acid,  562 
Phosphorus,  591,  601 

sesquisulphide,  593  (note) 
Phosphuretted  hydrogen,  592 
Physostigma,  320,  324 
Physostigmin,  320,  324 
Phytolacca,  434 
Phytolaccatoxin,  432 
Pichi,  77 
Picis  liquidae,  oleum,  405 

emplastrum  cantharidatum,  91,  728 
Picrsena,  58 
Picric  acid,  421 
Picroaconitine,  328 
Picropodophyllin,  103 
Picrotin,  431 
Picrotoxin,  431 
Pills,  40 

cathartic  vegetable,  105 
compound  cathartic,  105 
Pilocarpidine,  311  (note) 
Pilocarpine,  311,  326 
Pilocarpus,  311 
Pilulse,  40 

cathartic  vegetable,  105 
composite,  105 
Pimenta,  67 
Pimpernel,  scarlet,  707 
Pimpinella,  67 
Pineapple,  707 
Pink-root,  123 
Pinus,  86,  405 
Piper,  72 

angustifolium,  76 
cubeba,  75 
Piperazine,  549 
Piperidine,  72,  259,  262 
Piperine,  72 
Pipirinic  acid,  72 
Pipsissewa,  77 
Pitch,  Burgundy,  86,  728 

plaster,  86,  728 
Pituitary  gland,  718 
Pituri,  266 


INDEX. 


747 


Piturin,  266 

Fix  Burgundica,  86 

carbonis  and  liquida,  405 
Plasters,  30,  41,  727 

warming,  91 
Platinum,  698 
Plum  stones,  238  ^ 
Plumbi  suppositpria,  co ,  220 

cum  opio,  pilula,  220 
Plumbum,  670 
Plummets  pills,  633 
Podophyllotoxin,  103 
Podophyllum,  103,  105 
Poison  ivy  and  oak,  92 
Poisons,  17 
Pokeberry,  432 
Pokeroot,  435 
Polygala,  347 
Polygalic  acid,  347 
Polysolve,  351 
Pomegranate,  119 
Poplar,  413 
Poppy,  red,  55 
Port  wine,  145 
Potash,  540,  545 

water,  582 
Potassa,  545 

sulphurata,  575 
Potassium  acetate,  550 

action  of,  494 

arsenite,  617 

bicarbonate,  545 

bichromate,  699 

bitartrate,  536 

bromide,  500 

carbonate,  545 

chlorate,  522 

chloride,  494 

citrate,  531,  536 

dichromate,  699 

ferrocyanide,  539 

hydrate,  545 

hydroxidum,  545 

hypophosphite,  530 

iodate,  525 

iodide,  506 

lactate,  550 

malate,  531 

nitrate,  528 

nitrite,  464,  469 

oxalate,  553 

perchl  orate,  525 

permanganate,  589 

persulphate,  589 

phosphate,  531 

propionate,  550 

relation  of,  to  lime,  568 

salts,  494 

sozoiodolate,  519 

sulphate,  535 

sulphide,  575 

tartrate,  531 

thiosulphate,  530 

valerianate,  550 
Potato,  347 
Poultices,  41,  85 


Powders,  40 

bleaching,  583 

dusting-,  53 

Seidlitz,  537 
Precipitate,  white,  653 
Pregnancy,  26 
Preparations,  alcoholic,  39 

aqueous,  38 

pharmacopceial,  37 
Propionates,  550 
Propyl  alcohol,  126,  144 

nitrite,  464 
Protargol,  691 
Protocurarine,  254 
Protocuridine,  254 
Protocurine,  254 
Protopine,  206,  218,  227 
Protoplasm  poisons,  22 
Protoveratridine,  334,  337 
Protoveratrine,  334,  337 
Prune  stones,  238 
Prunes,  54 
Prunus  amygdala,  48 

laurocerasus,  238 

Virginiana,  67,  238 
Prussic  acid,  48,  68,  238 
Pseudaconitine,  328 
Pseudohyoscyamine,  277,  290 
Pseudojervine,  334 
Pseudomorphine,  206 
Pseudostrophanthin,  436 
Psychotria,  342 
Pterocarpi  lignum,  55 
Pterocarpus,  113 
Ptomatropine,  278 
Pulsatilla,  92 
Pulveres,  40 
Pulvis,  aromatic,  71 

effervescens  co.,  537 
Pumpkin  seed,  120 
Punica,  119 
Punicine,  119 
Purine  bodies,  244 
Purgatives,  93,  102 

anthracene,  98 

effervescing,  537 

oily,  97 

saline,  530 

vegetable,  93 
Purging  nuts,  97  (note) 
Pustulants,  78 
Pyoctanine,  423 
Pyrethric  acid,  72 
Pyrethrum,  72 
Pyridine,  35,  259,  262 
Pyrocatechin,  385,  396 
Pyrodine,  369 
Pyrogallol,  385,  402 
Pyrophosphates,  535 
Pyrovanadates,  701 
Pyroxylin,  728 

rvUAIKAMIDINE,  353  (note) 
\J     Quairamine,  353  (note) 
Quassia,  58,  116 
Quassiin,  55,  57,  58 


748 


INDEX. 


Quebracho,  352 
Quercus,  113 
Quicksilver,  634 
Quillaja,  347 
Quinamine,  353  (note) 
Quince,  Bengal,  59 

seeds,  48 
Quinetum,  364 
Quinidine,  353,  362 
Quinic  acid,  549 
Quinine,  353 

compared  with  antipyretics,  383 

hydrobromate,  504 

tasteless,  364 
Quinoidine,  364 
Quinoline,  35,  259,  262,  369 
Quinova  red,  353  (note) 
Quinovin,  353  (note) 

RASPBEEEY,  54 
Kealgar,  603 
Eectified  spirits,  145 
Eectum,  application  to,  31,  34, 40 
Kegional  anaesthesia,  308 
Eemijia,  353 
Eemote  action,  23 
Eesin,  87,  728 
Eesinous  purges,  103 
Eesins,  36 
Eesopyrin,  69 
Eesorcin,  385,  401 
Eesorcinol,  401 
Eevulsion,  theory  of,  78 
Ehamnus  purshiana,  102 
Ehatany,  112 
Eheum,  100 
Ehoeadine,  206 
Ehoeados  petala,  55 
Ehubarb,  99 
Ehus  glabra,  113 

radicans,  93 

toxicodendron,  92 
Eicin,  98,  720 
Eicinus,  98,  99,  720 
Eoburite,  421 
Eochelle  salt,  536 
Eosa,  67 
Eose  petals,  67 

Christmas,  435 
Eosemary,  oil  of,  68 
Eoses,  attar,  otto,  oil  of,  68 
Eosmarinse,  oleum,  68 
Eottlerin,  120 
Eubefacients,  78 
Eubidium,  495 
Eubijervine,  334 
Eubus,  113 

idseus,  54 
Eum,  72,  145 

CJABADILLA,  334,  339 
kJ     Sabadine,  334,  339 
Sabina,  67,  86 
Saccharides,  36 
Saccharin,  55 
Saccharum,  54 


Saccharum  lactis,  54 

Saffron,  55 

Safrol,  71 

Sage,  65,  67 

Salamander,  alkaloids  of,  36 

Salep,  48 

Salicin,  413 

Salicylates,  385,  386,  408 

Salicylic  acid,  76  (note),  385,  386,  408 

Saline  cathartics,  530 

Saliphen,  370,  380,  412 

Salipyrine,  369 

Salithymol,  386 

Salol,  386,  412 

Salophen,  370 

Salt  action,  481 

common,  486 

of  sorrel,  564 
Saltpetre,  528 
Salts,  481 

dissociation  of,  484 

ethereal,  127- 

purgative,  530 

smelling,  552 
Salumin,  697 
Salves,  30,  40 
Salvia,  67 

Sal  volatile,  spirit  of,  552 
Samandarine,  432 
Sambucus,  67 
Sandalwood,  74 

oil  of,  74 

red,  55 
Sanders,  55 
Sanguinaria,  227 
Sanguinarine,  227 
Santalol,  74 
Santalum  album,  76 

rubrum,  55 
Santonica,  122 
Santonin,  120 
Santoninoxim,  122 
Sapo,  86,  727 
Saponaria,  347 
Saponin,  346 
Saporubrin.  347 
Sapotoxin,  346 
Sarsse  radix,  351 
Sarsaparilla,  347 
Sarsaponin,  347 
Sassafras,  47,  67 
Sassy  bark,  435 
Saturnine  colic,  palsy,  673 
Saunders,  55 
Savine,  65,  68,  86 
Scammony,  103 
Schsenocaulon,  334 
Scheele's  green,  604 
Schleich's  infiltration  anaesthesia,  307 

mixtures,  179 

Schmiedeberg's  classification,  42 
Schweinfurth's  green,  604 
Scilla,  435 

pil.  ipecac,  cum,  220 
Scillain,  436 
Scillotoxin,  452 


INDEX. 


749 


Sclerotinic  acid,  472 
Seoparin,  264 

Scopolamine,  276,  289,  292 
Scopoleine,  277,  291 
Scopolia,  277,  291 

atropoides,  277,  291 
Scopoline.  276 
Scorpion,  721 
Scurvy  grass,  73 
Secale,  472 
Secaline,  473 
Secalintoxin,  473 
Secretions,  internal,  710 
Securite,  421 
Sedine,  72 
Sedum  acre,  72 
Seidlitz  powder,  537 
Selenium,  702 
Semecarpus,  92 
Senega,  347,  351 
Senegin,  347 
Senna,  99,  101,  102 
Sepia,  572 

Septentrionaline,  332 
Serpentaria,  59 
Serpentary,  57 
Sesame  oil,  51 
Sesquiterpenes,  61,  75 
Sevum,  50 

Sex,  influence  of,  on  dose,  26 
Sherry  wine,  145 
Sidonal,  549 
Silver,  624,  686 

colloid,  691 

nitrate,  686 
Sinalbin,  88 
Sinapis,  88 
Sinigrin,  88 

Size,  influence  of,  on  dose,  25 
Skin,  application  of  drugs  to,  30,  33 

irritants,  78 
Slippery  elm,  47 
Smilacin,  347 
Smilax,  347,  351 
Snake  poison,  721 

root,  59 
Soap,  86,  220,  727 

bark,  347,  351 

curd,  727 

hard,  727 

soft,  727 

Soaps,  compound  pill  of,  220 
Soapwort,  347 
Socaloin,  99 
Socatrine  aloes,  101 
Soda,  545 

chlorinated,  583 

water,  580 

Sodse  chloratse,  liquor,  583 
Sodium  acetate,  550 

arsenate,  617 

benzoate,  419 

bicarbonate,  545 

bisulphite,  530 

borate,  579 

bromate,  525 


Sodium  bromide,  500 

butyrate,  550 

cacodylate,  618  (note) 

caprylate,  550 

carbonate,  545 

chlorate,  522 

chloride,  486 

citrate,  536 

citrotartrate,  536 

ethylate,  545 

ferrocyanide,  531 

fluoride,  521 

fluorosilicate,  522 

formate,  550 

hydrate,  545 

hydroxide,  545 

hypophospite,  530 

hyposulphite,  530 

iodate,  525 

iodide,  506 

lactate,  550 

malate,  531' 

malonate,  554 

metacresotinate,  417 

nitrate,  528 

nitrite,  464,  469 

cenanthylate,  550 

orthocresotinate,  417 

oxalate,  553 

palmitate,  550 

paracresotinate,  417 

perchlorate,  525 

persulphate,  589 

phenolsulphonas,  417 

phosphate,  536 

proprionate,  550 

pyrophosphate,  536 

salicylate,  386,  408,  413 

silicate,  728 

sozoiodolate,  519 

stearate,  550 

succinate,  554 

sulphate,  531,  536 

sulphide,  573 

sulphite,  530 

sulphocarbolate,  386,  417 

sulphovinate,  537 

tartrate,  531,  536 

thiosulphate,  530 

valerianate,  550 
Soft  soap,  727 
Solanacese,  alkaloids,  277 
Solanein,  347 
Solanine,  346,  347 
Solanidine,  347 
Solanum,  347 
Solutions,  481 

antiseptic,  579 
Solutol,  400 
Solveol,  400 
Solvines,  351 
Soporifics,  186 
Sorrel,  salts  of,  564 
Sowbread,  347 
Sozoiodolates,  519 
Sozolic  acid,  417 


750 


INDEX. 


Spanish  fly,  89 
Sparteine,  259,  264 
Spartium,  264 
Spearmint,  67 

oil  of,  68 
Spermaceti,  51 
Spermine,  719 
Sphacelinic  acid,  472 
Sphacelotoxin,  473 
Spider  poison,  721 
Spigelia,  123 
Spirits,  71,  145 
Spiritus,  39 

frumenti,  145 

rectificatus,  145 

vini  gallici,  145 

of  volatile  oils,  69 
Spleen,  extract  of,  718 
Spruce  fir,  Norway,  86 
Squills,  435 

Squirting  cucumber,  103 
Stannous  salts,  701 
Staphisagria,  328,  333 
Star  anise,  67 

blazing,  347 
Starch,  45,  48,  51,  53 

glycerite,  51 
Stavesacre,  328,  333 

Stearates,  550  i 

Stearoptenes,  61,  426 
Stupe,  turpentine,  87 
Sterculia,  244 
Sternutatories,  31 
St.  Ignatius'  bean,  203 
Stibine,  633 
Stimulation,  20 

Stomach  and    intestine,  absorption    from, 
32 

administration  by,  30 
Stonecrop,  biting,  72 
Storax,  419 
Stramonium,  277,  29] 
Strontium,  572 

bromide,  504 

iodide,  510 

lactate,  550 

salicylate,  413 
Strophanthus,  435,  451 
Structure,   chemical  and    pharmacological 

action  of,  24 
Strychnine,  195,  203,  218 

comparison  with  atropine  and  caffeine, 

279 

with  digitalis,  455 
with  picrotoxin,  433 
Strychnos,  195,  203,  254 
Styptic  collodion,  112,  728 
Stypticine,  231 
Styrax,  419 

Subarachnoid  cocainization,  308 
Subcutaneous  injection,  33 
Sublimate,  corrosive,  650 
Succi,  40 
Succinates,  554 
Suet,  50 
Sugar,  45,  54 


Sugar  of  lead,  670 

Sulphanilic  acid,  512 

Sulphates,  535 

Sulphides,  573 

Sulphites,  529 

Sulphocarbolates,  386,  417,  685,  695 

Sulphonal,  127,  189,  192 

Sulphonmethanum,  192 

Sulphonmethylmethanum,  192 

Sulphovinate,  537 

Sulphur,  573 

flowers  of,  576 

iodide,  516 

milk  of,  576 

sublimated,  576 

washed,  576 

Sulphuretted  hydrogen,  575 
Sulphuric  acid,  560 

ether,  177 

Sulphuris,  hepar,  575 
Sulphurous  acid,  562 
Sumach,  113 

Currier's,  432 
Sumbul,  73 
Sundew,  707 
Suppositories,  40 
Suppository,  31 

glycerin,  52 

Suprarenal  capsule,  extract  of,  459 
Suprarennin,  459 
Swamp  dogwood,  422  (note) 
Swertia  chirata,  58 
Synergists,  28 
Syrupus,  39,  54 

aromaticus,  70 
Systemic  action,  23 
Syzygium,  725 

rp  A  BELIZE,  40 
1     Tablet  triturates,  40 
Taka-diastase,  708 
Talc,  53 
Tamarind,  54 
Tanacetum,  68 
Tanghinia,  437 
Tanghinin,  437 
Tannal,  697 
Tannalbin,  113 
Tannic  acid,  109 
Tannigen,  113 
Tannocol,  114 
Tannoform,  113 
Tannopin,  113 
Tansy,  68,  115 
Tar,  386,  405 
Tarantula,  721 
Taraxacum,  58 
Tartar,  cream  of,  535 

emetic,  79,  629 
Tartaric  acid,  559,  564 
Tartrates,  531 
Tea,  244,  252 
Teel  oil,  51 
Tellurates,  702 
Tellurium,  702 
Terebene,  86 


INDEX. 


751 


Terebinthina,  85 
Terpenes,  61,  86 
Terpin  hydrate,  86 
Testicle,  extract  of,  718 
Tetrachloride  of  carbon,  179 
Tetraiodpyrrol,  519 
Tetronal,  127,  191.  193 
Thalline,  369,  380 
Thallium,  701 
Thea,  244 

Thebaine,  195,  203,  206,217 
Theine,  244  (note) 
Theobroma,  244 
Theobromine,  244 
Theocine,  244 
Theon,  253 
Theophylline,  244 
Therapeutics,  17 
Thermifugine,  369 
Thermodine,  370,  380 
Thevetia,  435 
Thevetin,  436 
Thilanin,  576 
Thioform,  695 
Thiol,  387,  407 
Thiosinamine,  577 
Thiosulphates,  530 
Thornapple,  277 
Thujon,  426 
Thus  Americanum,  85 
Thyme,  66,  400 
Thymol,  66,  385,  400 
Thymolis  iodidum,  520 
Thymosalol,  412 
Thymus  extract,  718 
Thyreoglobulin,  711 
Thyreoiodin,  711   (note) 
Thyroid  extract,  711 
Thyroidism,  715 
Tin,  624,  701 
Tinctures,  39 
Tobacco,  266,  274,  281 

Indian,  266,  275 
Tolerance,  27,  720 
Tolu,  balsam  of,  419 
Toluifera,  419 
Toluol,  385,  392 
Tolutana  tinctura,  419 
Toluylendiamine,  422 
Toot  poison,  432 
Toughened  caustic,  690 
Toxalbumin,  98,  720 
Toxicodendrol,  92 
Toxicology,  17 
Toxiresin,"  432 
Tragacanth,  47 
Tribromphenol,  397 
Trichloracetic  acid,  563 
Trichlorphenol,  386 
Tricresol,  400 
Triiodocresol,  519 
Trimethyl-ammonium,  312,  499 
Trimethylamine,  126,  722 
Trinitrate  of  glycerin,  464 
Trinitrini,  liquor,  470 
Trional,  127,  191,  193 


Trioxybenzol,  402 
Triticum,  48 
Tritopine,  206 
Trituratio,  40, 105 
Trituration,  40 
Troches,  40 
Trochisci,  31,  40 
Tropacocaine,  299,  306 
Tropeines,  277,  290 
Tropic  acid,  276 
Tropine,  276 
Tubocurarine,  254 
Tully's  powder,  220 
Tumenol,  387 
Tungsten,  701 
Turlington's  balsam,  419 
Turpentine,  oil  of,  85 
Turpeth  mineral,  653 

ULMUS,  47 
Uncaria,  112 
Uncomocomo,  116  (note) 
Unguenta,  30,  40 
Unguentum,  50 
Upas  tree,  435 
Uranium,  701 
Urari,  254 
Urechites,  435 
Urethane,  127,  191,  193 
Urethra,  applications  to,  31 
Urethra!  suppositories,  40 
Urginea  maritima,  452 
Urosin,  549 

Urotropine,  76  (note),  425 
Ursion,  77 
Ustilago,  480 

Uterus,  applications  to,  31 
Uva  ursi,  77 

TTAGINA,  applications  to,  31 
Y      Vaginal  suppositories,  40 
Valerian,  73 
Valerianates,  551 
Vallet's  mass,  666 
Valyl,  74 
Vanadium,  701 
Vanilla,  67 
Vanillin,  71 
Vaseline,  50 
Vegetable  astringents,  109 

cathartic  pill,  105 

ferments,  707 

purgatives,  93 
Veratrine,  334 
Veratrum,  334 
Verbascum,  48 
Vermicides,  115 
Vermifuges,  115 
Verpnal,  127,  192,  193 
Vesicans,  collodium,  728 
Vesicants,  78 
Vienna  paste,  570 
Vina,  39 
Vinegar,  563 

medicated,  40 
Vini  gallici,  spiritus,  145 


752 


INDEX. 


Vinum  album,  145 

aurantii,  145 

rubrum,  145 

xericum,  145 
Vioform,  519 
Violet,  340 
Virginian  cherry,  67,  239 

prune,  67 
Volatile  oils,  61,  387,  426 

WAHOO,  105,  452 
Warburg's  tincture,  364 
Warming  plaster,  91,  728 
Wash,  black,  653 

yellow,  653 
Washes,  39,  653 
Water,  486 

aerated,  580 

glass,  728 

hemlock,  432 

potash,  580 

soda,  580 

Watering  places,  492 
Waters,  iron,  667 

medicated,  38 
Wax,  51,  727 

Weight,  influence  of,  on  dose,  25 
Whiskey,  72,  145 
Willow,  413 
Wine,  145 

Wines,  medicated,  39 
Wintergreen,  oil  of,  68,  386,  412 
Witchhazel,  113 
Wood  alcohol,  144 


Wood  tar,  386 
Wool  fat,  50 
Woorali,  254 
Woorara,  254 
Wormseed,  American,  124 

Levant,  122 
Wormwood,  65,  426 
Wristdrop,  673 

VANTHIN,  244 
A.     Xanthopsia,  121 
Xeroform,  695 
Xylol,  385,  392 


jasmine,  263 
I     sight,  121 
wash,  653 
Yerba  Mate,  244 
Young's  formula,  25 
Youpon,  244 
Yttrium,  495  (note) 

ZEA,  77 
Zinc,  624,  683 
Zinc  chloride,  685 

haemol,  685 

peroxide,  590 

phenolsulphonate,  685 

phosphide,  601 

sozoiodolate,  519 

sulphocarbolate,  417,  685 
Zincum,  685 
Zingiber,  67,  72 


